The close association between AIDS and non-Hodgkin's lymphoma (NHL) is well known. Few studies are available that evaluate the profile of NHL in a cohort of HIV-infected patients who reside in Puerto Rico. The present study was performed in a cohort of 2,843 HIV-infected patients followed in the Retrovirus Research Center at Bayamón, Puerto Rico, evaluated between January 1992 until December 2000. NHL prevalence was determined and differences between AIDS defining and non-AIDS defining NHL were evaluated with the Fisher and ANOVA test. NHL prevalence was 0.9%. Nine (33%) were AIDS-defining (AIDS-d) NHL and 18 (67%) were non-AIDS-d NHL. Both groups were similar in gender distribution and mean diagnosis age. The median CD4+ T cell count at diagnosis was below 150/mm3 in both groups. Injecting drug use was higher in AIDS-d NHL patients and Homo-Bisexual contact was higher in non-AIDS-d NHL patients. Death rate in the first year after the NHL was 67% in the AIDS-d group and 56% in the non-AIDS-d group. AIDS-d NHL incidence decreased after the implementation of combined antiretroviral therapy in the cohort, a finding not seen in the non-AIDS-d NHL. In summary the study detected low NHL prevalence, with high degree of immunological damage at the time of the lymphoma diagnosis. Conversely dissimilar response to the antiretroviral therapies was also perceived in the incidence of the two NHL groups.