Deletion of acetyl CoA carboxylase-2 (Acc2) reportedly causes leanness in the setting of hyperphagia. To determine the cellular basis for these effects, we generated a mouse model in which Acc2 can be selectively deleted by the action of Cre recombinase. Deletion of Acc2 from skeletal muscle, the predominant site of Acc2 expression, had no effect on body weight, food intake, or body composition. When Acc2 was inactivated in the germline, Acc2 knockout (Acc2KO) mice displayed no differences in body weight, food intake, body composition, or glucose homeostasis as compared to controls on chow or high fat diet. Total malonyl CoA content and fatty acid oxidation rates in skeletal muscle of Acc2KO mice were unchanged, suggesting metabolic compensation in response to the loss of Acc2. The limited impact of Acc2 deletion on energy balance raises the possibility that selective pharmacological inhibition of Acc2 for the treatment of obesity may be ineffective.