We investigated whether two alternative HOMA-IR thresholds recently proposed identify similar phenotype and have the same impact on gluco-metabolic risk. The two IR cutoffs, IR1 and IR2 (IR1: HOMA-IR >5.9 and IR2: HOMA-IR between 2.8 and 5.9 with HDL-C <51 mg/dl), were applied to a database of 2,360 outpatients, and their association with phenotypes, glucose tolerance, lipids and metabolic syndrome (MetS) was examined. IR1 group showed 5.5% of overweight versus 27.8% of IR2 subjects, and obesity was present in 92.3 versus 68.4%, respectively. We observed the major prevalence of pathological waist in IR1 compared to IR2 subjects: 96.0 versus 80.5% (p < 0.001). After OGTT, IR1 patients presented higher prevalence of impaired glucose tolerance (IGT: 25.8 vs. 20.2%, p < 0.001) and DM2 was diagnosed in 39.7% of IR1 versus 11.3% of IR2 patients (p < 0.001) with odds ratio (OR) 8.3 (95% CI 6.1-11.6) versus 0.8 (0.6-1.2), respectively. IR1 versus IR2 cutpoint showed higher significant (mean ± SEM) total cholesterol (224.8 ± 2.6 vs. 213.1 ± 1.7 mg/dl, p < 0.001) and triglyceride (208.1 ± 12.3 vs. 177.4 ± 4.8 mg/dl, p < 0.001) levels. MetS prevalence was significantly higher in IR1 than IR2 (89.0 vs. 78.3%, p < 0.001). The IR1 cutpoint was associated with a higher OR of MetS 7.3 (5.3-10.2) versus 5.2 (2.8-9.5) of IR2. In summary, the two alternative HOMA-IR cutoffs identify subjects with different distribution of phenotypes and gluco-metabolic risk. The IR1 patients are characterized by higher prevalence of obesity, pathological waist, MetS, dyslipidemia and IGT/DM2.