OBJECTIVE Determine the proportion of patients with chronic critical limb ischemia (CLI) who failed to adhere to Trans-Atlantic Inter-Society Consensus II guidelines of medical therapy and to quantify the effect of baseline suboptimal medical management on amputation-free survival (AFS). METHODS The patients were identified from a prospectively maintained database of consecutive patients presenting with CLI to the Vascular Surgery service at a single hospital. The primary outcome variable was AFS. The effects of baseline demographics, comorbid medical conditions, ambulatory status, optimal medical management, and Rutherford classification were assessed. Significant univariate predictors (P < .10) of AFS were entered into a multivariate Cox proportional hazards model. RESULTS From August 1, 2010 through January 1, 2012, 98 patients (median age, 59.0; interquartile range, 53, 64 years; 58 men) were evaluated with rest pain (n = 40) or tissue loss (n = 58). Optimal medical management was identified in 31 (32%) patients at initial presentation. Compliance rates for the entire cohort were 61% for statin use, 69% for antiplatelet therapy, 56% for angiotensin-converting enzyme inhibitor use, and 53% for beta-blocker use. Significant univariate predictors of major amputation or death included: Rutherford classification (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.01-2.41; P = .04); nonambulatory status (HR, 2.17; 95% CI, 1.68-2.81; P < .01); unrevascularized patients (HR, 2.77; 95% CI, 1.32-5.85; P < .01); a history of tobacco abuse (HR, 1.49; 95% CI, 0.57-3.86; P = .09); a history of end-stage-renal disease (HR, 7.97; 95% CI, 3.10-20.52; P < .01); suboptimal medical management (HR, 4.25; 95% CI, 1.28-14.07; P = .02); and an absence of antiplatelet agents (HR, 1.94; 95% CI, 0.92-4.11; P = .08). Independent predictors of major amputation or death included: initial nonambulatory status (HR, 2.43; 95% CI, 1.03-2.05; P < .01); unrevascularized status (HR, 2.43; 95% CI, 1.76-3.34; P = .01); and suboptimal medical management at presentation (HR, 8.54; 95% CI, 2.05-35.65; P < .01). CONCLUSIONS Despite guidelines advocating the optimization of atherosclerotic risk factors, less than one-third of patients with CLI present with their risk factors optimally managed. Patients who are medically undertreated have an eight-fold risk of major amputation and/or death. The magnitude of the effect suggests that future trials and quality assessments should stratify outcomes by the quality of baseline medical management. Of the risk factors affecting AFS medical therapy optimization is the variable that can be most significantly improved by vascular surgeons and the medical community.