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A considerable part of modern fauna and flora is in danger of extinction. The most severe threats are caused by environmental factors, such as habitat loss. Not all species are equally prone to extinction, however. Species’ intrinsic traits may also contribute to extinction risk, amplifying or attenuating the anthropogenic threats. The role of ecological traits, such as population size or range, in species extinctions has been well studied. The role of genetic factors remains more controversial. Here, we study the effect of genetic factors in comparison with the effect of body mass, which is known to be one of the strongest ecological determinants of extinction. Hence, if the signal from genetic factors is not lost even in the face of the major effect expected from body mass, this will provide strong evidence for the role of genetics in extinction. As a measure of the effect of genetics we chose the ratio of the rates of nonsynonymous (amino acid changing) to synonymous nucleotide substitutions, Ka/Ks. This ratio can be identified with the probability of fixation of a deleterious mutation (with selection coefficient s < 0) relative to the probability of fixation of a neutral mutation (with s = 0), and thus reflects the efficiency of selection against deleterious mutations. Accordingly, under s < 0, the closer the Ka/Ks to 1, the weaker is the purifying selection on nonsynonymous substitutions and the greater is the chance that such substitutions, most of which are slightly deleterious, will accumulate and thus contribute to extinction. The material contains complete mitochondrial genomes of 211 mammalian species, each of which is characterized by Ka/Ks, body mass W and the level of extinction risk. As a measure of risk we used the species’ affiliation to any one of the five groups of risk recognized by the IUCN Red List. This provides us with a polytomous variable of the five levels of risk, which are: Least Concern (LC), Near Threatened (NT), Vulnerable (VU), Endangered (EN) and Critically Endangered (CR). Using LC group as the reference, we constructed a set of logistic-regression relationships of the polytomous dependent variable of extinction risk on ln(Ka/Ks) and lnW. We found that the pair of groups, LC and EN, is particularly suitable to assess the role of nonsynonymous substitution rate and body mass in extinction risk. Next, therefore, we obtained a logistic relationship of the dichotomous variable of EN vs. LC on ln(Ka/Ks) and lnW. Finally, we estimated the effect of a one-sigma increase in ln(Ka/Ks) and separately a one-sigma increase in lnW on the resulting increase in extinction risk. We found that body mass is responsible for a 62% (±13%) increase in extinction risk and nonsynonymous substitutions for a 38% (±13%) increase in extinction risk, the latter being 1.6 times smaller than the former. We conclude that nonsynonymous nucleotide substitutions, most of which are likely to be deleterious, contribute significantly to mammalian extinctions, even when the effect of ecological factors represented by body mass has been taken into account.