OBJECTIVE Once-daily intravenous cefazolin with probenecid is used commonly to treat cellulitis. The primary objective of this study was to determine the risk factors of treatment failure with this regimen. METHODS This was a retrospective cohort study of adult outpatients with cellulitis who were initially treated with once-daily intravenous cefazolin plus probenecid. Treatment failure is defined as inadequate improvement that necessitates either hospital admission or a change in antibiotic therapy to a different intravenous regimen. A stepwise logistic regression analysis was performed to determine the risk factors for regimen failure. RESULTS From January 2003 to December 2008, 159 patients with cellulitis were initially treated with once daily intravenous cefazolin plus probenecid. Thirty-five (22%) patients had treatment failure. The treatment for 53% (9/17) of the patients with a history of chronic venous disease (CVD) failed, whereas the treatment for 18% (26/142) of patients without CVD failed (P = 0.001). Multivariate analysis identified the presence of CVD as the only risk factor associated with treatment failure (odds ratio 4.4, 95% confidence interval 1.5-13; P = .007). CONCLUSIONS Patients with cellulitis and CVD who are being treated with once-daily intravenous cefazolin plus probenecid should be monitored closely for treatment failure.