Free fatty acids (FFA) have been shown in vitro to inhibit insulin-mediated glucose uptake by muscle and have been proposed as in vivo mediators of peripheral insulin resistance. Twenty percent fat emulsion and heparin were administered to six awake healthy dogs during 3-hr insulin clamp studies. Lipid infusion resulted in a fivefold increase in FFA concentration over control (2371 +/- 331 vs 439 +/- 65, P less than 0.002), but did not importantly alter glucose and insulin concentrations. No change was observed in glucose disposal (13.30 +/- 1.41 vs 13.76 +/- 1.51 mg/kg . min control), hindquarter A-V glucose concentration difference (9 +/- 2 vs 9 +/- 1 mg/dl), or hindquarter glucose uptake (3.42 +/- 0.84 vs 3.71 +/- 0.65 mg/kg . min). These observations suggest that FFA may not be important mediators of peripheral insulin resistance in critically ill patients.