The purpose of this study was to examine the relationship among pain and depression, hopelessness, and quality of life in human immunodeficiency virus (HIV)-infected gay men, taking into account the role of HIV symptoms. One hundred sixty-one HIV+ gay men were assessed, with 40 men endorsing HIV- related pain. The HIV+ men with pain had a modal rating of pain within the mild range. They had significantly more advanced disease, more physical and depressive symptoms, and reported less life satisfaction than the men without pain. However, when HIV illness variables are accounted for, the higher depression scores in the men with pain were largely accounted for by somatic rather than cognitive symptoms. While pain is associated with greater physical distress in this cohort of HIV-seropositive gay men, it does not appear to be independently associated with cognitive symptoms of depression. These findings apply to HIV-infected men with mild pain and may not apply to those who experience more severe pain. Nonetheless, these observations highlight the overlap between symptoms of depression and pain and the challenge that clinicians face in assessing patients suffering from pain.