The Rh blood group system is a human blood group system. It contains proteins on the surface of red blood cells. After the ABO blood group system, it is most likely to be involved in transfusion reactions. The Rh blood group system consisted of 49 defined blood group antigens in 2005. As of 2023,^[update] there are over 50 antigens, of which the five antigens D, C, c, E, and e are among the most prominent. There is no d antigen. Rh(D) status of an individual is normally described with a positive (+) or negative (−) suffix after the ABO type (e.g., someone who is A+ has the A antigen and Rh(D) antigen, whereas someone who is A− has the A antigen but lacks the Rh(D) antigen). The terms Rh factor, Rh positive, and Rh negative refer to the Rh(D) antigen only. Antibodies to Rh antigens can be involved in hemolytic transfusion reactions and antibodies to the Rh(D) and Rh antigens confer significant risk of hemolytic disease of the newborn.

The Rh blood group system has two sets of nomenclature: one developed by Ronald Fisher and R. R. Race, the other by Wiener. The two systems reflect different theories of inheritance. The Fisher–Race system, which is currently more common, uses the CDE nomenclature. This system is based on the theory that a separate gene controls the product of each corresponding antigen (e.g., a "D gene" produces D antigen, and so on). However, the d gene was hypothetical, not actual.

The Wiener system uses the Rh–Hr nomenclature. This system is based on the theory that there is one gene at a single locus on each of the two copies of chromosome 1, each contributing to production of multiple antigens. In this theory, a gene R₁ is supposed to give rise to the "blood factors" Rh₀, rh′, and rh″ (corresponding to modern nomenclature of the D, C, and E antigens) and the gene r to produce hr′ and hr″ (corresponding to modern nomenclature of the c and e antigens).

Notations of the two theories are used interchangeably in blood banking (e.g., Rho(D) meaning RhD positive). Wiener's notation is more complex and cumbersome for routine use. Because it is simpler to explain, the Fisher–Race theory has become more widely used.^{[citation needed]}

DNA testing has shown that both are partially correct: There are in fact two linked genes, the RHD gene which produces a single immune specificity (anti-D) and the RHCE gene with multiple specificities (anti-C, anti-c, anti-E, anti-e). Thus, Wiener's postulate that a gene could have multiple specificities (something many did not give credence to originally) has been proved to be correct. On the other hand, Wiener's theory that there is only one gene has proved to be incorrect, as has the Fisher–Race theory that there are three genes, rather than the two. The CDE notation used in the Fisher–Race nomenclature is sometimes rearranged to DCE to more accurately represent the co-location of the C and E encoding on the RhCE gene, and to make interpretation easier.^{[citation needed]}

The proteins which carry the Rh antigens are transmembrane proteins, whose structure suggests that they are ion channels. The main antigens are D, C, E, c and e, which are encoded by two adjacent gene loci, the RHD gene which encodes the RhD protein with the D antigen (and variants) and the RHCE gene which encodes the RhCE protein with the C, E, c and e antigens (and variants). There is no d antigen. Lowercase "d" indicates the absence of the D antigen (the gene is usually deleted or otherwise nonfunctional).^{[citation needed]}

Rh phenotypes are readily identified through the presence or absence of the Rh surface antigens. As can be seen in the table below, most of the Rh phenotypes can be produced by several different Rh genotypes. The exact genotype of any individual can only be identified by DNA analysis. Regarding patient treatment, only the phenotype is usually of any clinical significance to ensure a patient is not exposed to an antigen they are likely to develop antibodies against. A probable genotype may be speculated on, based upon the statistical distributions of genotypes in the patient's place of origin.^{[citation needed]}

R₀ (cDe or Dce) is today most common in Africa. The allele was thus often assumed in early blood group analyses to have been typical of populations on the continent, particularly in areas below the Sahara. Ottensooser et al. (1963) suggested that high R₀ frequencies were likely characteristic of the ancient Judean Jews, who had emigrated from Egypt prior to their dispersal throughout the Mediterranean Basin and Europe on the basis of high R₀ percentages among Sephardi and Ashkenazi Jews compared to native European populations and the relative genetic isolation of Ashkenazim. However, more recent studies have found R₀ frequencies as low as 24.3% among some Afroasiatic-speaking groups in the Horn of Africa, as well as higher R₀ frequencies among certain other Afroasiatic speakers in North Africa (37.3%) and among some Palestinians in the Levant (30.4%). On the contrary, at a frequency of 47.2% of the population of Basque country having the lack of the D antigen, these people display the highest frequency of the Rh negative phenotype.