Humoral immunity is the aspect of immunity that is mediated by macromolecules – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. Humoral immunity is named so because it involves substances found in the humors, or body fluids. It contrasts with cell-mediated immunity. Humoral immunity is also referred to as antibody-mediated immunity.

The study of the molecular and cellular components that form the immune system, including their function and interaction, is the central science of immunology. The immune system is divided into a more primitive innate immune system and an acquired or adaptive immune system of vertebrates, each of which contain both humoral and cellular immune elements.

Humoral immunity refers to antibody production and the coinciding processes that accompany it, including: Th2 activation and cytokine production, germinal center formation and isotype switching, and affinity maturation and memory cell generation. It also refers to the effector functions of antibodies, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.

The concept of humoral immunity developed based on the analysis of antibacterial activity of the serum components. Hans Buchner is credited with the development of the humoral theory. In 1890, Buchner described alexins as "protective substances" that exist in the blood serum and other bodily fluids and are capable of killing microorganisms. Alexins, later redefined as "complements" by Paul Ehrlich, were shown to be the soluble components of the innate response that leads to a combination of cellular and humoral immunity. This discovery helped to bridge the features of innate and acquired immunity.

Following the 1888 discovery of the bacteria that cause diphtheria and tetanus, Emil von Behring and Kitasato Shibasaburō showed that disease need not be caused by microorganisms themselves. They discovered that cell-free filtrates were sufficient to cause disease. In 1890, filtrates of diphtheria, later named diphtheria toxins, were used to vaccinate animals in an attempt to demonstrate that immunized serum contained an antitoxin that could neutralize the activity of the toxin and could transfer immunity to non-immune animals. In 1897, Paul Ehrlich showed that antibodies form against the plant toxins ricin and abrin, and proposed that these antibodies are responsible for immunity. Ehrlich, with his colleague von Behring, went on to develop the diphtheria antitoxin, which became the first major success of modern immunotherapy. The discovery of specified compatible antibodies became a major tool in the standardization of immunity and the identification of lingering infections.

Antibodies or Immunoglobulins are glycoproteins found within blood and lymph. Structurally, antibodies are large Y-shaped globular proteins. In mammals, there are five types of antibodies: immunoglobulin A, immunoglobulin D, immunoglobulin E, immunoglobulin G, and immunoglobulin M. Each immunoglobulin class differs in its biological properties and has evolved to deal with different antigens. Antibodies are synthesized and secreted by plasma cells that are derived from the B cells of the immune system.

An antibody is used by the acquired immune system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target. By binding their specific antigens, antibodies can cause agglutination and precipitation of antibody-antigen products, prime for phagocytosis by macrophages and other cells, block viral receptors, and stimulate other immune responses, such as the complement pathway.

An incompatible blood transfusion causes a transfusion reaction, which is mediated by the humoral immune response. This type of reaction, called an acute hemolytic reaction, results in the rapid destruction (hemolysis) of the donor red blood cells by host antibodies. The cause is usually a clerical error, such as the wrong unit of blood being given to the wrong patient. The symptoms are fever and chills, sometimes with back pain and pink or red urine (hemoglobinuria). The major complication is that hemoglobin released by the destruction of red blood cells can cause acute kidney failure.