Background: A high-protein diet is one of the maneuvers which produce hypertrophy of kidney mass. The underlying mechanism(s) has not been elucidated. In the present study, we investigated the possibility that a humoral factor may be involved. Methods: Twenty-eight 3-week-old Charles River rats were studied. Fourteen underwent right nephrectomy and 14 sham operation. Each of these groups was divided into two equal subgroups (n = 7 in each): one maintained on a regular diet (20% protein) and the other on a high-protein diet (60% protein) for 7 days. Following this period the animals were sacrificed. Sera from the animals were added to mesangial cell cultures from kidneys of intact 3-week-old rats, and the thymidine incorporation was assessed. Results: The parameters of kidney mass indicated that the high-protein diet indeed produced kidney hypertrophy. Sera from the sham-nephrectomized animals fed a high-protein diet produced a significantly greater proliferative effect on mesangial cells in culture than sera from the respective animals on a normal-protein diet. Sera from either nephrectomized group or from the high-protein sham-operated group all had similar magnitudes of enhancement of mesangial cell proliferation. Conclusion: We conclude that the renal hypertrophy produced by a high-protein diet is mediated, at least in part, by a humoral factor(s).