Abstract Background: Inflammation and focal atrophy are common features adjacent to prostate tumors. Limited evidence exists on whether these features have prognostic significance. Methods: In the Health Professionals Follow-Up Study and Physicians' Health Study, we studied 1,035 men diagnosed with prostate cancer. A genitourinary pathologist centrally reviewed tumor and normal areas of hematoxylin and eosin slides from prostate cancer specimens for the presence of acute and chronic inflammation, and four subtypes of focal atrophy. Cox proportional hazards models adjusted for potential confounders were used to estimate HRs and 95% confidence intervals (CI) for the association of these features with lethal prostate cancer, defined as development of metastatic disease or death during follow-up. Results: During a median of 12 years of follow-up, 153 men developed lethal prostate cancer. A total of 84% of men had histologic evidence of chronic inflammation and 30% had acute inflammation. Both chronic and acute inflammation were inversely associated with lethal prostate cancer in age- and lifestyle-adjusted models. Chronic inflammation remained inversely associated with lethal prostate cancer after additionally adjusting for prognostic clinical features (HR = 0.45; 95% CI, 0.30–0.69 for mild and HR = 0.51; 95% CI, 0.33–0.80 for moderate to severe). None of the atrophic lesions were associated with lethal prostate cancer. Conclusions: Our data suggest that the presence of inflammation, particularly chronic inflammation, in prostate cancer tissue is associated with better prognosis among patients with prostate cancer. Impact: This is the largest prospective cohort study to examine the association between inflammation, focal atrophy, and lethal prostate cancer.