Despite the major role of insulin in regulating apolipoprotein C-III (apo C-III) production, little is known about the relationship between apo C-III and insulin resistance. We examined this relationship, and the association of apo C-III with dyslipidemia, in a triethnic sample of 168 subjects with normoglycemia or type 2 diabetes. African-Americans had lower triglycerides (1.21 +/- 0.11 mmol/l) compared with Hispanics (2.01 +/- 0.14 mmol/l) and white non-Hispanics (1.83 +/- 0.15 mmol/l), regardless of gender and type 2 diabetes status (P < 0.01), but this difference was partially accounted for by ethnic difference in apo C-III levels. Metabolic syndrome was associated with high apo C-III (> 14 mg/dl) in Hispanics (OR = 5.6; 95%CI: 1.3-23.4) and white non-Hispanics (OR = 6.9; 95%CI: 1.3-36.4), but not in African-Americans. Apo C-III was the best predictor of triglycerides (R2 = 0.54, P < 0.001), after accounting for demographic and clinical variables. We found an inverse relationship between apo C-III levels and low-density lipoprotein (LDL) particle size in the type 2 diabetes subjects with (r = -0.36, P = 0.02) and without (r = -0.47, P = 0.02) the metabolic syndrome, but in normoglycemic subjects an inverse relationship was evident only in metabolic syndrome subjects (r = -0.52, P < 0.01). These results suggest that higher apo C-III may contribute to the increased cardiovascular risk in subjects with insulin resistance and type 2 diabetes through its effects on triglycerides and LDL particle size.