Background: UV radiation (UVR) exposure is the primary risk factor for basal cell carcinoma (BCC). Although prescription diuretics have photosensitizing properties, the relationship between diuretic use and BCC remains unclear. Methods: Using data from the United States Radiologic Technologists Study, a large, nationwide prospective cohort, we assessed the relationship between diuretic use and first primary BCC while accounting for sun exposure history, constitutional characteristics, lifestyle factors, and anthropometric measurements for geographically dispersed individuals exposed to a wide range of ambient UVR. Results: After adjustment for potential confounders, we found a significantly increased risk of BCC associated with diuretic use [HR, 1.22; 95% confidence interval (CI), 1.07-1.38]. This relationship was modified by body mass index (P = 0.019), such that BCC risk was increased with diuretic use in overweight (HR, 1.43; 95% CI, 1.16-1.76) and obese individuals (HR, 1.43; 95% CI, 1.09-1.88), but not in normal weight individuals (HR, 0.99; 95% CI, 0.81-1.21). Conclusions: Increased risk of BCC associated with diuretic use in overweight and obese participants may be related to higher dosages, longer duration of medication use, reduced drug metabolism, or drug interactions. Impact: Future cohort studies should obtain more detailed information on medication use, consider factors that affect drug metabolism, and measure intermediate endpoints such as photosensitivity reactions.