The antipsychotic drug haloperidol has antiproliferative and growth-inhibiting properties on prostate cancer cell lines in vitro by binding the sigma 1 protein. Evidence is needed regarding a possible preventive association in men. To examine whether our epidemiologic data support an inverse association of haloperidol use with risk of prostate cancer. These case-control analyses used conditional logistic regression to estimate relative risk by odds ratios (ORs) adjusting for race/ethnicity and aspects of medical care related to detection of prostate cancer. We tested 3 other commonly used antipsychotic drugs, risperidone, quetiapine, and olanzapine, for sigma 1 protein binding and inhibition of clonogenic growth of prostate cancer cells. Use of any of these by men was considered use of a comparator drug. 1) association of haloperidol with prostate cancer; 2) sigma 1 binding and clonogenic growth. Probably owing to small numbers of haloperidol recipients, evidence of a preventive association was inconsistent, depending on the definition of long-term use. If duration of use was greater than 1 year, the odds ratio (OR) was 0.38 (95% confidence interval (CI) = 0.14-1.01) for haloperidol and 0.80 (95% CI = 0.66-0.98) for the comparator drug; if the duration of use was greater than 2 years, the OR was 0.66 (95% CI = 0.24-1.76) for haloperidol and 0.84 (95% CI = 0.66-1.08) for the comparator drug. Unlike haloperidol, risperidone, quetiapine, and olanzapine did not bind sigma 1 or inhibit clonogenic growth. Given the laboratory evidence, our ambiguous epidemiologic findings should encourage more epidemiologic evaluation of haloperidol use and risk of prostate cancer. Finding a negative association could be a scientific advance in prostate cancer prevention but would not be sufficient basis for recommending the prescription of haloperidol for that purpose.