Disease associations of HTLV-II are poorly defined, despite a high seroprevalence among injection drug users (IDU). One hundred twenty-four HTLV-II-seropositive emergency room and clinic patients were matched by age, sex, and clinic to 120 HTLV-I/II-seronegative patients. Medical records were reviewed blinded to HTLV-II status, and International Classification of Disease 9th Clinical Modification (ICD-9CM)-coded diagnoses were compared between seropositive patients and controls. After adjustment for relevant confounding variables such as human immunodeficiency virus infection, HTLV-II-seropositive IDU had an increased risk of bacterial pneumonia (odds ratio [OR], 3.45; 95% confidence interval [CI], 1.58, 7.56), abscess (OR, 8.30; 95% CI, 4.02, 17.11), and lymphadenopathy (OR, 3.91; 95% CI, 1.24, 12.32) compared with HTLV-II-negative non-IDU patients. In contrast, HTLV-II-negative IDU were at only marginally increased risk of the same conditions, with OR of 1.76 (95% CI, 0.42, 7.40), 3.00 (95% CI, 0.94, 9.59), and 1.31 (95% CI, 0.15, 11.66), respectively. These results indicate that HTLV-II seropositivity may define a subgroup of IDU who are at particularly high risk of bacterial pneumonia, skin and soft tissue abscess, and lymphadenopathy. Whether HTLV-II has an etiologic role in predisposing IDU to bacterial infections and lymphadenopathy will require further investigation.