Purpose Prior research is mixed as to whether long-term cancer survivors (LCSs) have higher rates of depression than the general population. This is the first study to compare the rates of major depressive disorder (MDD) between LCSs and people without cancer histories in a nationally representative cross-sectional multistage cluster survey sample, the National Comorbidity Survey-Replication (NCS-R). Methods Between 2001 and 2003, face-to-face interviews were conducted for the NCS-R in a national sample of 9,282 people, of whom 5,692 were assessed for a history of cancer. Participants with cancer diagnoses at least 5 years before the interview were considered LCSs. Survivors of childhood cancers were excluded. Comparing LCSs to those without a cancer history, odds ratios for having a MDD episode in the last 12 months before interview were obtained using multiple logistic regression controlling for demographic and medical variables. Differences in characteristics of those MDD episodes were also compared between groups. Results Of participants age 23 years or older, 243 LCSs and 4,890 adults without a cancer history were identified in the sample. Adjusting for demographic variables and medical comorbidities, LCSs did not have increased odds of MDD in the last 12 months, with an odds ratio of (OR) 0.99 (95% CI, 0.55 to 1.79). LCSs reported higher mean levels of impairment from MDD in their home, social, and work life, but these differences were not significant. Conclusion LCSs do not appear to have elevated rates of MDD. However, they may experience greater impairment from MDD compared to those without cancer. Longitudinal studies are needed to confirm these findings.