We investigated the association between free fatty acid (FFA) concentration and ventricular premature complexes (VPCs) in nonischemic patients with non-insulin-dependent diabetes mellitus using 3 approaches: cross-sectional analysis (n = 142), intervention including induction of elevated FFA levels with Intralipid heparin (n = 15), and reduction in FFA levels with Acipimox (n = 34) and a longitudinal follow-up study (n = 59). Patients at the third tertile of fasting plasma FFA concentration had the strongest increase in VPCs. Independently of age, sex, body mass index (BMI), waist/hip ratio, left ventricular mass index, glycated hemoglobin, fasting plasma insulin and triglyceride concentration, and daily physical activity, FFA concentration and VPCs were significantly correlated (r = 0.21 p <0.01). At multiple logistic regression analysis independently of age, sex, BMI, waist/hip ratio, left ventricular mass index, mean arterial blood pressure, glycated hemoglobin, fasting plasma insulin, triglycerides and potassium concentration, fasting plasma low-density lipoprotein/high-density lipoprotein cholesterol ratio, and daily physical activity, plasma FFA concentration was a significant determinant of VPCs (odds ratio 1.2, 95% confidence interval 1.0 to 2.3). Intralipid infusion (10% in 24 hours) (n = 15) and acipimox administration (250 mg, 4 times/day) (n = 34) increased, and decreased fasting plasma FFA concentration, respectively. In those studies, change in VPCs paralleled the effects on plasma FFA. In the longitudinal study (n = 59), plasma FFA concentration predicted the development of VPCs (RR 1.4 95% confidence interval 1.0 to 1.9) independently of age, sex, BMI, waist/hip ratio, left ventricular mass index, mean arterial blood pressure, fasting plasma triglyceride concentration, fasting plasma low-density lipoprotein/high-density lipoprotein cholesterol ratio, and daily physical activity. In conclusion, in nonischemic patients with non-insulin-dependent diabetes mellitus, plasma FFA concentration is associated with the frequency of ventricular premature complexes.