The high concentration of zinc in the prostate suggests that zinc may play a role in prostate health. We examined the association between supplemental zinc intake and prostate cancer risk among 46 974 U.S. men participating in the Health Professionals Follow-Up Study. During 14 years of follow-up from 1986 through 2000, 2901 new cases of prostate cancer were ascertained, of which 434 cases were diagnosed as advanced cancer. Supplemental zinc intake at doses of up to 100 mg/day was not associated with prostate cancer risk. However, compared with nonusers, men who consumed more than 100 mg/day of supplemental zinc had a relative risk of advanced prostate cancer of 2.29 (95% confidence interval = 1.06 to 4.95; Ptrend = .003), and men who took supplemental zinc for 10 or more years had a relative risk of 2.37 (95% confidence interval = 1.42 to 3.95; Ptrend<.001). Although we cannot rule out residual confounding by supplemental calcium intake or some unmeasured correlate of zinc supplement use, our findings, that chronic zinc oversupply may play a role in prostate carcinogenesis, warrant further investigation.