Episodes of acute infection are thought to deplete body stores of vitamin A. The mechanism by which this might occur is not known, but increased metabolic requirements are presumed to play a role. We have found, however, that significant amounts of retinol and retinol-binding protein (RBP) were excreted in the urine during serious infections, whereas only trace amounts were found in the urine of healthy control subjects. The geometric mean excretion rate in 29 subjects with pneumonia and sepsis was 0.78 mumol retinol/d. Subjects with fever (temperature > or = 38.3 degrees C) excreted significantly more retinol (geometric mean = 1.67 mumol/d) than did those without fever (0.18 mumol/d; t = 3.53, P < 0.0015). Aminoglycoside administration and low glomerular filtration rates (< 35 mL/min) were also associated with higher rates of urinary retinol excretion. Thirty-four percent of patients excreted > 1.75 mumol retinol/d, equivalent to 50% of the US recommended dietary allowance. These data show that vitamin A requirements are substantially increased during serious infections because of excretion of retinol in the urine, and suggest that these losses are due to pathologic changes associated with the febrile response.