OBJECTIVE We sought to document the secondary failure rate of metformin monotherapy in a clinical practice setting and to explore factors that predict therapeutic failure. RESEARCH DESIGN AND METHODS We studied 1,799 type 2 diabetic patients who, between 2004 and 2006, lowered their A1C to <7% after initiating metformin monotherapy as their first-ever anti-hyperglycemic drug. We examined all A1C values recorded through 31 December 2008 (2-5 years of follow-up), defining secondary failure as a subsequent A1C > or =7.5% or the addition or substitution of another anti-hyperglycemic agent. We used logistic regression to identify factors associated with the probability of secondary failure. RESULTS Of the 1,799 patients studied, 42% (n = 748) experienced secondary failure; the mean failure rate was 17% per year. However, patients who initiated metformin within 3 months of diabetes diagnosis failed at an age-and A1C-adjusted rate of 12.2% (10.5-14.4%) per year, and patients who initiated while A1C was <7% failed at an adjusted rate of 12.3% per year. An interaction term between duration of diagnosed diabetes and A1C was not significant. Age, duration, and A1C at initiation were the only factors that predicted secondary failure. CONCLUSIONS Although metformin failure may occur more rapidly in clinical practice than in clinical trails, initiating it soon after diabetes diagnosis and while A1C is low might preserve beta-cell function, prolong the effectiveness of metformin, reduce lifetime glycemic burden, and prevent diabetes complications. Our findings support the current treatment algorithm for hyperglycemia management that recommends metformin initiation when diabetes is first diagnosed.