Social monogamy is rare in mammals, but in those species in which it occurs, individuals frequently engage in extra-pair copulation (EPC). Numerous hypotheses have been proposed to explain EPC, but relatively few field studies have examined factors influencing EPC in socially monogamous mammals. Prairie voles (Microtus ochrogaster) are a socially monogamous rodent in which extra-pair paternity (EPP) is common. Using genetic data from a 3-year study of a natural population of prairie voles, we investigated whether the negative consequences of inbreeding and the structure of social units (male–female pairs vs. groups; adult sex ratio within groups) were factors affecting EPC. We found strong evidence that genetic similarity between males and females that produced offspring via EPC was less than that between social partners, as would be expected if avoiding inbreeding depression influenced the occurrence of EPC. Social unit structure was also a factor involved with extra-pair parentage. Contrary to our expectations, the greater the proportion of females in the group, the lower the chance of EPC resulting in offspring production by females, and, similarly, the chance of EPP by males declined as the proportion of males within the group increased. However, neither males nor females were more likely to produce offspring from EPC when they were living in pairs versus groups. One implication of these results is that EPC may be influenced more by female behaviors, such as mate choice, than male mate guarding. Overall, our results suggest that the proximate factors influencing EPC in prairie voles are complex but include the cost of inbreeding depression and the structure of social units.