Apnea intervals frequently occur in premature infants. Periods of apnea occur more often with decreases in gestational age. Periods of apnea can cause damage to the infant's developing brain and other organs. This study was designed to investigate the preventive effects of caffeine on apnea incidence in higher-risk neonates. Methods: In this single-center randomized control trial study, premature infants with a birth weight of ≤1200 g were eligible for enrollment. Twenty-six infants were randomly assigned to receive 20 mg/kg caffeine, as the loading dose, which was followed by 5 mg/kg daily as the maintenance dose until the 10th day of life; these infants were compared with 26 infants in the control group. Primary outcomes were incidence of apnea, bradycardia, and cyanosis. Results: Fifty-two infants were enrolled (26 in the caffeine group and 26 in the control group). The preventive effect of caffeine on apnea was significant in these infants. The relative risk for incidence of apnea in preterm neonates with a birth weight of <1200 g was 0.250 (95% confidence interval, 0.097–0.647). Only four infants (15.4%) in the caffeine group developed apnea, compared with 16 (61.5%) in the control group (p = 0.001). Conclusion: It seems that preventative effects of caffeine on apnea become apparent by using the drug in very premature infants.