The objective of this study was to undertake a retrospective analysis of claims data of diabetic foot ulcer (DFU) patients to determine the rates of amputation and identify the risk and protective factors. Rates of amputation were calculated in patients diagnosed with DFU in the MEDSTAT Marketscan database between January 2000 and December 2002, who had prediagnosis coverage of 90 days. A nested case-control study was conducted using a 1 : 10 ratio of amputee cases to randomly selected nonamputee controls matched on follow-up days. The association of co-morbid conditions, demographic factors, and severity (5+ outpatient claims for DFU) on amputation was estimated by adjusted odds ratios (AOR) with 95% confidence intervals (CIs). The 5911 eligible patients yielded an incidence density rate of 2.30 amputations per 100 person years (95% CI = 1.91, 2.77). The 116 cases and 1153 controls averaged 307.3 and 308.5 observation days, respectively. Amputation was significantly increased by male gender (AOR 1.98), Charlson co-morbidity scores of 4-5 and 6+ (AOR = 2.89 and 5.36, respectively), renal disease (AOR = 2.11), peripheral vascular disease (AOR = 2.67), and 5+ outpatient DFU services (AOR = 2.17). Practitioners may consider more aggressive care and earlier referral to specialists for DFU patients who fit risk profiles for amputation, which include peripheral vascular disease, multiple co-morbid conditions, and repeated outpatient DFU services.