Southern sea otter (Enhydra lutris nereis) population recovery is influenced by a variety of factors, including predation, biotoxin exposure, infectious disease, oil spills, habitat degradation, and resource limitation. This population has also experienced a significant genetic bottleneck, resulting in low genetic diversity. We investigated how two metrics, familial relatedness and genetic diversity, are correlated with common causes of mortality in southern sea otters, including cardiomyopathy, acanthocephalan (Profilicollis spp.) peritonitis, systemic protozoal infection (Toxoplasma gondii and Sarcocystis neurona), domoic acid intoxication, end-lactation syndrome, and shark bite. Microsatellite genetic markers were used to examine this association in 356 southern sea otters necropsied from 1998 to 2012. Significant associations with genetic diversity or familial relatedness (P<0.05) were observed for cardiomyopathy, acanthocephalan peritonitis, and sarcocystosis, and these associations varied by sex. Adult male cardiomyopathy cases (n=86) were more related than the null expectation (P<0.049). Conversely, female acanthocephalan peritonitis controls (n=110) were more related than the null expectation (P<0.004). Including genetic diversity as a predictor for fatal acanthocephalan peritonitis in the multivariate logistic model significantly improved model fit; lower genetic diversity was associated with reduced odds of sea otter death due to acanthocephalan peritonitis. Finally, male sarcocystosis controls (n=158) were more related than the null expectation (P<0.011). Including genetic diversity in the multivariate logistic model for fatal S. neurona infection improved model fit; lower genetic diversity was associated with increased odds of sea otter death due to S. neurona. Our study suggests that genetic diversity and familial relatedness, in conjunction with other factors such as age and sex, may influence outcome (survival or death) in relation to several common southern sea otter diseases. Our findings can inform policy for conservation management, such as potential reintroduction efforts, as part of species recovery.