Study Type--Therapy (outcomes research) Level of Evidence 2b. What's known on the subject? and What does the study add? Comorbid diabetes can affect prostate cancer treatment decision-making and outcomes. Few longitudinal studies have investigated the effect of comorbid diabetes on general and cancer-specific health-related quality of life (HRQL) in prostate cancer. Our study found that men with prevalent diabetes (pre-prostate cancer diagnosis) generally had the poorest general HRQL, urinary control and sexual function scores over time, independent of treatment. Non-diabetic men had the best scores and men with incident diabetes (post-prostate cancer diagnosis) reported intermediate scores. OBJECTIVE • To investigate the association between prostate cancer, diabetes, and long-term general and cancer-specific health-related quality of life (HRQL) in a cohort of men with non-metastatic prostate cancer. PATIENTS AND METHODS • We used data from self-administered surveys to assess the HRQL of men with localized or locally advanced disease at 6 (baseline), 12, 24, and 60 months after initial diagnosis. • We examined changes in general and cancer-specific HRQL with repeated measures analyses using a mixed-model approach. RESULTS • In total, we evaluated 1811 men, including 13% with prevalent (pre-prostate cancer diagnosis) diabetes, 12% with incident (post-prostate cancer diagnosis) diabetes, and 75% who never reported being diagnosed with diabetes. • Generally, men with prevalent diabetes had the poorest scores on general HRQL and non-diabetic men the best scores, independent of treatment. • Similarly, men with prevalent diabetes had the lowest urinary control and sexual function scores over time, while men without diabetes had the highest scores. Men with incident diabetes reported intermediate scores. CONCLUSION • Prostate cancer survivors with comorbid diabetes have poorer general and cancer-specific HRQL than those without diabetes.