Non-Hodgkin's lymphoma is the 2nd most common malignancy in human immunodeficiency virus (HIV)-infected patients. However, limited information regarding head and neck manifestations of non-Hodgkin's lymphoma is present in the literature. The aim of this article is to describe the head and neck manifestations of non-Hodgkin's lymphoma in HIV-infected patients and compare it with that seen in noninfected patients. A case-control study was performed including 124 patients with non-Hodgkin's lymphoma presenting over a 5.5-year period to tertiary care center in a metropolitan location. Overall, the anatomic distribution of non-Hodgkin's lymphoma is not altered in the presence of HIV infection with the head and neck region (63%) most often involved overall. However, within the head and neck region, extralymphatic disease is significantly more common in HIV-infected patients (59%) than noninfected patients (33%; P = .001). Central nervous system (CNS) involvement accounts for 41% of head and neck non-Hodgkin's lymphoma in HIV-infected patients, in contrast to only 12% of noninfected patients. High-grade lymphoma (68%) are more common than intermediate (30%) or low-grade disease (2%) in the HIV-infected population, whereas low (24%) and intermediate (60%) grades are more common than high-grade lymphoma (16%) in noninfected patients (P < .001). The large cell immunoblastic type (48%) is the most common subtype in HIV-infected patients, whereas diffuse large-cell type (32%) was most common in HIV-negative patients (P < .05). Survival is significantly poor for HIV-infected patients (P < .05). The impact of HIV infection on survival remain significant even after controlling for the effects of confounding factors. Head and neck involvement with non-Hodgkin's lymphoma occurs in a significant number of HIV-infected patients. Our data show that the distribution and course of non-Hodgkin's lymphoma is unique in HIV-infected patients. A high level of suspicion for non-Hodgkin's lymphoma is required in all cases of head and neck lesions in patients with HIV infection to facilitate management.