A decreased metabolic rate has been associated with decreased ventilatory response to hypoxia and hypercapnia, and also with starvation. We fed a 500-calorie carbohydrate diet with supplemental electrolytes, designed to simulate alimentation by usual intravenous fluids, to seven normal subjects for 10 days to determine the effect of semi-starvation on metabolic rate and ventilatory responses. By the 10th day metabolic rate was significantly decreased, and hypoxic ventilatory response decreased to 42% of control (P less than 0.05). In two subjects, hypoxic ventilatory response was virtually abolished at day 10. These changes reversed toward normal with refeeding. The decrease in hypoxic ventilatory response response was significantly (P less than 0.01) related to the decrease in metabolic rate. Hypercapnic ventilatory response, measured as the slope of the ventilatory response to hypercapnia, decreased slightly but not significantly. The decrease in hypoxic ventilatory response seen during semi-starvation may contribute to the hypoxemia and respiratory failure subsequent to caloric restriction.