An unexpected association between history of vasectomy and increased risk of prostate cancer emerged when multiple comparisons were carried out in data collected from 1976-1988 in a US hospital-based case-control study of many diseases and exposures. The association was assessed in detail in these data, in a comparison of 220 men with first episodes of prostate cancer with 571 noncancer controls and 960 cancer controls. The age-adjusted relative risk of prostate cancer was 5.3 (95% confidence interval 2.7-10) when noncancer controls were used and 3.5 (95 percent confidence interval 2.1-6.0) when cancer controls were used. The magnitude of the relative risk estimate appeared to be unrelated to the length of the interval after vasectomy. Allowance for several factors did not alter the estimates, but we did not have information on testosterone level or sexual activity, which may have been confounding factors. The association was stronger among men most likely to have been under more intensive medical surveillance; selective detection of asymptomatic cancer in such men would have led to an excess of cases. Further studies are needed to rule out chance, bias from medical surveillance, and uncontrolled confounding as explanations for the finding.