Expedient weaning of infants from the respirator minimizes the risk of complications associated with assisted ventilation. Since theophylline and caffeine decrease apnea and enhance respiratory effort, we conducted a blinded, randomized comparative evaluation of each drug to determine extubation time and incidence of reintubation. Forty-five clinically stable premature infants receiving mechanical ventilation on minimal settings randomly were assigned to receive either theophylline (n = 23) or caffeine (n = 22) at least 1 day before and 5 days after extubation. From study entry to extubation, the mean number of days was 2.7 for both theophylline- and caffeine-treated infants. Three theophylline- and three caffeine-treated infants developed respiratory failure necessitating reintubation (NS). These findings indicate that for premature infants on minimal respiratory settings, the duration of intubation and the incidence of reintubation after treatment with theophylline or caffeine were similar.