The incidence of systemic non-Hodgkin lymphoma (NHL) has only slightly decreased since the introduction of highly active antiretroviral therapy (HAART), suggesting that current antiretroviral strategies do not eliminate the lymphoma risk. This study evaluates the evolving characteristics of HIV and NHL between the pre-HAART and the post-HAART periods in 246 HIV-infected NHL patients from a single institution. Major HIV-related characteristics were similar in the two periods. Most patients in the post-HAART period presented with unknown (23%), untreated (16%), or uncontrolled (37%) HIV infection. Despite an increased frequency of advanced stage IV disease in the post-HAART period (68% vs. 53%, p =.03), the overall survival has improved, with a 2-year survival probability of 61.6% versus 35.9%, (p <.001). This was associated with an increased complete remission rate (69% vs. 55%, p =.04) and the generalization of more intensive chemotherapy regimens. Most patients (76%) who developed NHL in the post-HAART period had uncontrolled HIV replication. However, 27 patients (24%) developed NHL despite an effective viral suppression at NHL diagnosis. Patients who were naive to any antiretroviral therapy at NHL diagnosis had an overall survival probability very similar to that of patients with controlled HIV replication. Improvement in the overall survival rate in the post-HAART period was associated with more intensive chemotherapy regimens, increased complete remission rate, and a likely benefit of continuation or introduction of HAART.