BACKGROUND: Skin/soft tissue infections (SSTIs) are the leading cause of hospital admissions among injection drug users (IDUs). METHODS: We performed a retrospective investigation to determine the epidemiology of SSTIs (ie, cellulitis and/or abscesses) in febrile IDUs, with a focus on bacteriology and potential predictors of increased health care utilization measured by longer length of stay and rehospitalization. Subjects were drawn from a cohort of febrile IDUs presenting to an inner-city emergency department from 1998 to 2004. RESULTS: Of the 295 febrile IDUs with SSTIs, specific discharge diagnoses were cellulitis only (n = 143, 48.5%), abscesses only (n = 113, 38.3%), and both (n = 39, 13.2%). Documented HIV infection rate was 28%. Of note, 10 subjects were newly diagnosed with HIV infection during their visits. Staphylococcus aureus was the leading pathogen, and increasing rates of methicillin-resistant S. aureus emerged over time (before 2001: 4%, 2001-2004: 56%, P < 0.01). HIV seropositivity predicted rehospitalization within 90 days [adjusted hazard ratios and 95% confidence intervals: 2.90 (1.20 to 7.02)]. HIV seropositivity also predicted increased length of stay in those who were nonbacteremic [adjusted hazard ratios and 95% confidence intervals: 1.49 (1.11 to 2.01)]. CONCLUSIONS: Among febrile IDUs with SSTIs, a strong association between HIV seropositivity and health care resource utilization was found. Accordingly, attention to HIV serostatus should be considered in clinical disposition decisions for this vulnerable high-risk population.