Across species, diversity at the major histocompatibility complex (MHC) is critical to individual disease resistance and, hence, to population health; however, MHC diversity can be reduced in small, fragmented, or isolated populations. Given the need for comparative studies of functional genetic diversity, we investigated whether MHC diversity differs between populations which are open, that is experiencing gene flow, versus populations which are closed, that is isolated from other populations. Using the endangered ring‐tailed lemur (Lemur catta) as a model, we compared two populations under long‐term study: a relatively “open,” wild population (n = 180) derived from Bezà Mahafaly Special Reserve, Madagascar (2003–2013) and a “closed,” captive population (n = 121) derived from the Duke Lemur Center (DLC, 1980–2013) and from the Indianapolis and Cincinnati Zoos (2012). For all animals, we assessed MHC‐DRB diversity and, across populations, we compared the number of unique MHC‐DRB alleles and their distributions. Wild individuals possessed more MHC‐DRB alleles than did captive individuals, and overall, the wild population had more unique MHC‐DRB alleles that were more evenly distributed than did the captive population. Despite management efforts to maintain or increase genetic diversity in the DLC population, MHC diversity remained static from 1980 to 2010. Since 2010, however, captive‐breeding efforts resulted in the MHC diversity of offspring increasing to a level commensurate with that found in wild individuals. Therefore, loss of genetic diversity in lemurs, owing to small founder populations or reduced gene flow, can be mitigated by managed breeding efforts. Quantifying MHC diversity within individuals and between populations is the necessary first step to identifying potential improvements to captive management and conservation plans.