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AIDS-related primary central nervous system lymphoma (AR-PCNSL) has a poor prognosis. Improved understanding of specific patient, infectious, diagnostic, and treatment-related factors that affect overall survival (OS) is required to improve outcomes.Population-based registry linkage study.Adult cases from the San Francisco AIDS registry (1990–2000) were matched with the California Cancer Registry (1985–2002) to ascertain AR-PCNSL data. Survival time was assessed through 31 December 2007. Risk factors and temporal trends for death were measured using two-sided Kaplan–Meier and Cox analyses.Two hundred and seven AR-PCNSL patients were identified: 68% were white, 20% Hispanic, 10% African–American, and 2% Asian. Nineteen percent of patients had central nervous system (CNS) opportunistic infections diagnosed prior to AR-PCNSL. Fifty-seven percent of patients received radiation and/or chemotherapy and 12% used HAART prior to or within 30 days of AR-PCNSL diagnosis. One hundred and ninety-nine patients died (34 deaths/100 person-years). In adjusted analysis, prior CNS opportunistic infection diagnosis increased risk of death (hazard ratio 1.9, P = 0.0006) whereas radiation and/or chemotherapy decreased risk (hazard ratio 0.6, P < 0.0001). AR-PCNSL diagnosis 1999–2002 had a lower mortality risk (hazard ratio = 0.4, P = 0.02) compared to 1990–1995. African–Americans had an increased risk of death compared to whites or Asians (hazard ratio = 2.0, P = 0.007).OS among AR-PCNSL patients improved over time but remains poor, especially among African–Americans. Prospective evaluation of curative therapy in AR-PCNSL is urgently needed. Accurate diagnosis of CNS mass lesions in patients with AIDS is required and for those with AR-PCNSL, antiretroviral therapy with concomitant AR-PCNSL therapy, and antimicrobial supportive care may improve OS.