OBJECTIVES: We sought to evaluate which risk factors may be implicated in prolonged duration of antibiotic treatment in hospitalized patients with complicated skin and structure infections (cSSSI). METHODS: We pooled data from two double-blind, randomized, multinational, clinical trials among patients with cSSSI. Patients were randomly assigned to receive either tigecycline (initial 100mg dose, followed by 50mg twice daily) or vancomycin with aztreonam (1g vancomycin plus 2g aztreonam, twice daily) via IV administration. Treatment termination was based on physician assessment of resolution of signs and symptoms of infection, with formal test of cure (TOC) at least 12-days later. We used a Cox proportional hazard (CPH) model to identify potential clinical risk factors for longer time-to-treatment termination. RESULTS: Among 1041 patients in the modified intent-to-treat (m-ITT) population with complete hospitalization data, deep/extensive cellulitis (59%) was the most common cSSSI diagnosis, spontaneous infection (51%) was the typical etiology, and diabetes (22%) was the most common comorbidity. No significant differences were observed in baseline characteristics. Median treatment duration was eight-days for each treatment group. The estimated CPH model identified diabetes (p<.0001), female sex (p=0.017), infected ulcer (p=0.001), and use of concomitant antibiotics (p=0.002) as independent risk factors for significantly longer treatment duration. Adjusting for these risk factors, tigecycline was associated with a trend toward shorter treatment duration overall (p=0.072) and within the diabetes, infected ulcer, and female strata. There was no difference across the treatment groups in the rate of cure at the TOC visit (p=0.197). CONCLUSIONS: Diabetes, female sex, infected ulcers, and use of concomitant antibiotics emerged as significant risk factors for prolonged treatment duration in cSSSI. Tigecycline, the first in a new antibiotic class, the glycylcyclines, was associated with a trend toward shorter treatment duration, once the risk factors were adjusted for.