Experimental and clinical data suggest that aspirin and other nonsteroidal inflammatory drugs may delay the progression of prostate cancer through inhibition of the COX pathway and its effects on cellular proliferation, apoptosis, and angiogenesis. Epidemiologic data support a reduced risk of prostate cancer incidence with aspirin use, yet no evidence exists about whether aspirin after diagnosis influences progression or survival. We conducted a prospective study of 3,986 participants of the Health Professionals Follow-up Study, with a prostate cancer diagnosis between January 1, 1990, and December 31, 2005. We used Cox proportional hazards regression to evaluate the association between aspirin use after diagnosis and the development of metastases or fatal prostate cancer through January 31, 2008, adjusting for risk factors associated with incidence and mortality in this cohort, prediagnostic aspirin use, Gleason score, tumor-node-metastasis (TNM) stage, and primary treatment. In total, 265 men developed bony or other organ metastases or fatal prostate cancer during the 18 years of follow-up. We observed no association between updated aspirin use after diagnosis and lethal prostate cancer [tablets/week: <2: HR, 1.12; 95% confidence interval (CI), 0.72-1.72; 2-5: HR, 1.05; 95% CI, 0.62-1.80; ≥ 6: HR, 1.08; 95% CI, 0.76-1.54; P(trend) = 0.99]. The results remained unchanged when we examined aspirin use at baseline only (P(trend) = 0.70) or frequency of use (d/wk; P(trend) = 0.35) or limited the outcome to fatal prostate cancer (P(trend) = 0.63). There was no association between aspirin use after a prostate cancer diagnosis and lethal disease in this cohort of prostate cancer survivors.