The objective of this study was to examine the effect of socioeconomic status and insurance status on health-related quality of life (HRQOL) outcomes in men with prostate cancer. The design was a retrospective cohort study using multiple sites, including both academic and private practice settings. A cohort of 860 men with newly diagnosed, biopsy-proven prostate cancer of any stage was identified within CaPSURE, a longitudinal disease registry of prostate cancer patients. HRQOL was assessed with validated instruments, including the RAND 36-item Health Survey (SF-36) and the UCLA Prostate Cancer Index. Covariates included insurance status, education level, annual income, age, stage, comorbidity, Gleason grade, baseline PSA, marital status, ethnicity and primary treatment. HRQOL measurements were taken at 3-6-month intervals. Analysis of covariance was used to determine the effect of SES and insurance status on the HRQOL domains at baseline and over time. Patients with lower annual income had significantly lower baseline HRQOL scores in the all of the domains of the SF-36 and four of eight disease-specific HRQOL domains. No relationship was seen between annual income and HRQOL outcomes over time. Conversely, health insurance status was associated with HRQOL over time, but not at baseline. Health insurance status appears to have a unique effect on general HRQOL outcomes in men after treatment for prostate cancer. This study confirms the commonly held belief that patients of lower SES tend to have worse quality of life at baseline and following treatment for their disease. These findings have important ramifications for clinicians, researchers and policy makers.