HIV-infected persons treated with highly active antiretroviral therapy (HAART) continue to have elevated risk for non-Hodgkin lymphoma (NHL). We conducted a retrospective cohort study of NHL among patients at an urban HIV clinic (N = 3025). Proportional hazards models identified immunologic and virologic predictors of NHL. Sixty-five NHLs arose during 1989 to 2006. NHL incidence declined over time. Nonetheless, 51 NHLs (78%) occurred within the HAART era (1996-2006). NHL risk increased with declining CD4 count (P trend < 0.0001) and increasing HIV viral load (P trend = 0.005). In a multivariable model, NHL risk was independently associated with both current CD4 count (hazard ratios 7.7 and 3.8, respectively, for CD4 counts 0-99 and 100-249 vs. 250+ cells/mm(3); P trend < 0.0001) and prior time spent with a viral load above 5.00 log(10) copies/mL (hazard ratios of 3.4, 2.6, and 6.8, respectively, for 0.1-0.4, 0.5-1.4, and 1.5+ yr vs. 0 yr; P trend = 0.004). Although serum globulin levels were elevated compared with the general population, NHL risk was unrelated to this B-cell activation marker (P = 0.39). Among HIV-infected individuals in the HAART era, NHLs are linked to immunosuppression and extended periods of uncontrolled HIV viremia. The association with high-level viremia could reflect detrimental effects on immune function related to incompletely effective HAART or direct effects on B cells.