Background: Although we continue to make progress in reducing the incidence and mortality for most cancers in the United States, African Americans (AA) continue to experience higher cancer incidence rates and have worse survival than other populations. The causes of these poorer outcomes, from higher mortality to poorer quality of life, in AA cancer survivors are not well understood. The Detroit ROCS study was initiated to improve our understanding of the experience of AAs living with cancer. Methods: 1,000 AA and non-Hispanic white (NHW) patients with primary lung, female breast, prostate or colorectal cancer diagnosed on or after January 1, 2013, and/or treated at the Karmanos Cancer Institute in Detroit, MI were recruited to participate in a cohort study with planned follow-up for 4 years. At baseline, participants completed a web-based survey to gather information about their medical history, family history of cancer, treatment and medication use, behavioral risk factors and self-assessed quality of life. Statistical analyses were performed to examine racial differences in the distribution of patient characteristics including comorbid conditions, stage at diagnosis, first course treatment and reported health-related quality of life (HRQOL). Results: The majority of patients were AA (60%) and female (61%), with a median age at diagnosis of 60 years. AAs were older, more likely to report use of cigarettes and alcohol and report a greater number of comorbidities compared with NHW patients; they were less educated and less likely to be employed full time or married (all p-values < 0.001). AA patients reported poorer overall HRQOL compared with NHW patients (p-value < 0.001). Controlling for marital status and employment attenuated the observed racial differences in mean HRQOL scores across all measured domains. Conclusions: We observed significantly lower self-reported HRQOL among AA cancer survivors compared with NHW, which could be partially explained by differences in specific socioeconomic factors but interestingly, not the presence of multiple comorbidities. Future research efforts will evaluate the relative contribution of social and financial support to HRQOL in AAs.