Although primary central nervous system (CNS) lymphoma was considered part of the spectrum of AIDS from the outset, systemic non-Hodgkin's lymphoma is considered a rather late manifestation of HIV infection. Any group at risk for AIDS may develop HIV-related lymphoma, and the characteristics of disease in all groups appear identical. The majority of these lymphomas are of the high-grade, B-cell types, including B-immunoblastic lymphoma and small noncleaved, Burkitt or non-Burkitt. Advanced, extranodal disease is seen at diagnosis in the majority of patients, who often present with widespread disease involving multiple organs. Central nervous system disease may be seen in the absence of systemic lymphoma ("primary CNS lymphoma") and carries a particularly poor prognosis. Leptomeningeal involvement is the most common central nervous system manifestation of systemic HIV-related lymphoma, and its presence does not imply a worse prognosis. Although very intensive regimens of multiagent chemotherapy have been employed in patients with HIV-related lymphoma, several studies indicate that these patients may not be able to tolerate such dose intensity. Newer regimens, employing lower dose-intensive regimens with early CNS prophylaxis, may be effective in inducing remissions in approximately half of treated individuals, who may attain long-term, lymphoma-free survival.