The effects of prolonged fasting on the composition of weight loss and the rates of muscle protein synthesis and degradation were compared in obese and nonobese (lean) rats. Lean rats weighting 400 g could survive 60 days of fasting whereas obese rats weighing 550 g could survive 60 days. Weight loss was similar in both phenotypes over the first 10 days of fasting (15 g/day), but the composition of weight loss differed. Obese rats lost nearly twice as much lipid but only one-fifth as much body protein as lean rats. The fasting metabolic rate [kilocalories/(day . kilograms 0.75)] was similar in both phenotypes. This finding indicates a slower decline in metabolic rate during fasting in obese rats, since maintenance requirements are greater in lean rats. In fed rats, the fractional rates of muscle protein synthesis (FRS) and breakdown (FRB) were slightly higher in obese rats. Fasting reduced muscle protein synthesis in both phenotypes. In obese rats, however, the FRS declined more slowly than in lean rats. On the other hand, FRB decreased in fasted obese rats but greatly increased in fasted lean rats. It was concluded that the better protein retention and slower decline in metabolic rate in fasted obese rats were related to their different regulation of muscle protein synthesis and breakdown during fasting.