In organic chemistry, Zaytsev's rule (or Zaitsev's rule, Saytzeff's rule, Saytzev's rule) is an empirical rule for predicting the favored alkene product(s) in elimination reactions. While at the University of Kazan, Russian chemist Alexander Zaytsev studied a variety of different elimination reactions and observed a general trend in the resulting alkenes. Based on this trend, Zaytsev proposed that the alkene formed in greatest amount is that which corresponded to removal of the hydrogen from the alpha-carbon having the fewest hydrogen substituents. For example, when 2-iodobutane is treated with alcoholic potassium hydroxide (KOH), but-2-ene is the major product and but-1-ene is the minor product.

More generally, Zaytsev's rule predicts that in an elimination reaction the most substituted product will be the most stable, and therefore the most favored. The rule makes no generalizations about the stereochemistry of the newly formed alkene, but only the regiochemistry of the elimination reaction. While effective at predicting the favored product for many elimination reactions, Zaytsev's rule is subject to many exceptions. Many of them include exceptions under Hofmann product (analogous to Zaytsev product). These include compounds having quaternary nitrogen and leaving groups like NR₃⁺, SO₃H, etc. In these eliminations the Hofmann product is preferred. In case the leaving group is halogens, except fluorine; others give the Zaytsev product.^{[clarification needed]}

Alexander Zaytsev first published his observations regarding the products of elimination reactions in Justus Liebigs Annalen der Chemie in 1875. Although the paper contained some original research done by Zaytsev's students, it was largely a literature review and drew heavily upon previously published work. In it, Zaytsev proposed a purely empirical rule for predicting the favored regiochemistry in the dehydrohalogenation of alkyl iodides, though it turns out that the rule is applicable to a variety of other elimination reactions as well. While Zaytsev's paper was well referenced throughout the 20th century, it was not until the 1960s that textbooks began using the term "Zaytsev's rule".

Zaytsev was not the first chemist to publish the rule that now bears his name. Aleksandr Nikolaevich Popov published an empirical rule similar to Zaytsev's in 1872, and presented his findings at the University of Kazan in 1873. Zaytsev had cited Popov's 1872 paper in previous work and worked at the University of Kazan, and was thus probably aware of Popov's proposed rule. In spite of this, Zaytsev's 1875 Liebigs Annalen paper makes no mention of Popov's work.

Any discussion of Zaytsev's rule would be incomplete without mentioning Vladimir Vasilyevich Markovnikov. Zaytsev and Markovnikov both studied under Alexander Butlerov, taught at the University of Kazan during the same period, and were bitter rivals. Markovnikov, who published in 1870 what is now known as Markovnikov's rule, and Zaytsev held conflicting views regarding elimination reactions: the former believed that the least substituted alkene would be favored, whereas the latter felt the most substituted alkene would be the major product. Perhaps one of the main reasons Zaytsev began investigating elimination reactions was to disprove his rival. Zaytsev published his rule for elimination reactions just after Markovnikov published the first article in a three-part series in Comptes Rendus detailing his rule for addition reactions.

The hydrogenation of alkenes to alkanes is exothermic. The amount of energy released during a hydrogenation reaction, known as the heat of hydrogenation, is inversely related to the stability of the starting alkene: the more stable the alkene, the lower its heat of hydrogenation. Examining the heats of hydrogenation for various alkenes reveals that stability increases with the amount of substitution.

The increase in stability associated with additional substitutions is the result of several factors. Alkyl groups are electron donating by inductive effect, and increase the electron density on the sigma bond of the alkene. Also, alkyl groups are sterically large, and are most stable when they are far away from each other. In an alkane, the maximum separation is that of the tetrahedral bond angle, 109.5°. In an alkene, the bond angle increases to near 120°. As a result, the separation between alkyl groups is greatest in the most substituted alkene.

Hyperconjugation, which describes the stabilizing interaction between the HOMO of the alkyl group and the LUMO of the double bond, also helps explain the influence of alkyl substitutions on the stability of alkenes. In regards to orbital hybridization, a bond between an sp² carbon and an sp³ carbon is stronger than a bond between two sp³-hybridized carbons. Computations reveal a dominant stabilizing hyperconjugation effect of 6 kcal/mol per alkyl group.