OBJECTIVE: To describe secondary failure of initial metformin therapy in patients who achieved initial HbA(1c) (A1C) <8% and to identify predictors of failure. RESEARCH DESIGN AND METHODS: We identified 1,288 patients who achieved A1C <8% within 1 year of initiating metformin as their first-ever antihyperglycemic drug. Subjects were followed until they added/switched antihyperglycemics, they terminated health plan membership, or 31 December 2004. We defined secondary failure using two separate but overlapping approaches: 1) addition/switch to another antihyperglycemic drug or 2) first A1C measurement >8.0% after at least 6 months on metformin. RESULTS: The best A1C achieved within 1 year of metformin initiation was the most powerful predictor of avoiding secondary failure. Approximately 50% of subjects whose best A1C was 7-7.9% added/switched antihyperglycemic drugs within 36 months, whereas it took >60 months for those in the 6-6.9% A1C category to reach a 50% failure rate. Those who achieved an A1C <6% did not reach a 50% rate of adding/switching drugs until 84 months. For the alternative secondary failure outcome, about half of those whose best A1C was 7.0-7.9% reached an A1C >8% within 24 months. Only approximately 25% of subjects in the 6-6.9% category failed by 48 months, and >80% of subjects in the <6% category remained below 8% through 60 months. CONCLUSIONS: Whether defined by adding/switching to another drug or by reaching an A1C of 8%, secondary failure is inversely associated with the reduction of A1C achieved within the 1st year of metformin monotherapy.