α‐Methylacyl‐CoA racemase (AMACR) is an enzyme that serves as a diagnostic biomarker of prostate cancer in clinical practice. Recent studies suggest that low AMACR expression is associated with biochemical recurrence and the development of fatal disease.

We conducted a prospective cohort study among 920 men aged 47–84 years, who were diagnosed with prostate cancer in the Physicians' Health Study and the Health Professionals Follow‐up Study cohorts, and whose resected tissue specimens were available for immunohistochemical analysis. We used Cox proportional hazards regression to evaluate the association of AMACR expression with lethal prostate cancer over a 20‐year follow‐up period.

In total, 68 men died from prostate cancer, and an additional 18 developed bony metastases during follow‐up. We found that lower AMACR intensity was associated with higher prostate‐specific antigen levels (P = 0.003) and more advanced clinical stage (P = 0.06) at diagnosis, and a nonsignificant trend for higher risk of lethal outcomes. The hazard ratio (HR) comparing the lowest to the highest quartile of AMACR expression intensity was 1.53 ((95% CI: 0.86–2.73), P‐for‐trend across quartiles = 0.07); this trend was further attenuated after adjustment for age, Gleason score, stage, and cohort with a HR of 1.24 (95% CI: 0.69–2.22), P‐for‐trend = 0.23.

Low AMACR expression in primary tumor specimens was not independently associated with the development of metastatic and lethal prostate cancer after treatment over a 20‐year follow‐up period, after adjustment for important clinical covariates at diagnosis. Prostate 72:301–306, 2012. © 2011 Wiley Periodicals, Inc.