Objective To assess whether African-Americans are at increased risk of developing peripartum cardiomyopathy. Background Peripartum cardiomyopathy is a heart disease of unknown cause that affects young women, often with devastating consequences. The frequency of peripartum cardiomyopathy varies markedly between African and non-African regions. Methods A case-control study was performed at a regional center that provides medical care to a racially heterogeneous population. For each case, 3 normal control patients were randomly selected that delivered babies within the same month. Results African-American women had a 15.7-fold higher relative risk of peripartum cardiomyopathy than non-African-Americans (odds ratio (OR) 15.7, 95% confidence interval (CI): 3.5–70.6). Other significant univariate risk factors were hypertension (OR 10.8, CI: 2.6–44.4), being unmarried (OR 4.2, 95% CI: 1.4–12.3), and > 2 previous pregnancies (OR 2.9, CI: 1.1–7.4). African-American ethnicity remained a significant risk factor for peripartum cardiomyopathy when other risk factors were considered in multivariable (OR 31.5, CI: 3.6–277.6) and stratified analyses (OR range 12.9–29.1, p<0.001). Although the frequency of peripartum cardiomyopathy (185 per 100,000 deliveries) at this center was higher than previous U.S. reports, it was comparable to the frequency in countries with more women of African descent (100–980 per 100,000). Analysis of other U.S. studies confirmed that the frequency of peripartum cardiomyopathy was significantly higher in African-American women. Conclusions African-American women have significantly higher odds of developing peripartum cardiomyopathy that could not be explained by several other factors. Further research will be necessary to determine the potential environmental and/or genetic factors associated with African descent that confer this risk.