Objective To study the efficacy and safety of different doses of caffeine citrate and aminophylline treatment for apnea of prematurity. Methods Preterm infants who met the inclusive criteria were admitted to NICU of JingZhou Central Hospital from October 1st, 2013 to October 1st, 2015. They were randomly assigned to three groups. Infants assigned to high dose caffeine group were received a loading dose of 40 mg / kg daily, followed by the maintaining dose of 20 mg / kg daily. Neonates in low dose caffeine group were administered with the loading dose of 20 mg / kg daily, followed by maintaining dose of 10 mg / kg daily. Infants in the aminophylline group received a loading dose of 5 mg / kg, then with maintaining dose of 2 mg / kg every 12 hours. Caffeine citrate or aminophylline therapy were continued until the infants were free from apnea for a period of 7 days or when the gestational age of 34 weeks were reached. Extubation failure rate, frequency of apnea, duration of apnea, mechanical ventilation, as well as oxygen therapy, length of hospital stay, mortality, and the adverse effects were compared among three groups. Results 90 infants were enrolled for study, with 30 in each group. Extubation failure rate, frequency of apnea, apnea duraion and oxygen therapy duration of infants in high dose caffeine groups were all significantly lower than those of infants in low dose caffeine group and aminophylline group (P < 0. 05). The incidence of tachycardia was significantly higher in the high dose caffeine group compared to the other two groups (P < 0. 05). Whereas all these factors between low dose caffeine group and aminophylline group were of no statistical difference (P > 0. 05). Duration of mechanical ventilation and CPAP, length of hospital stay, incidence of complications (BPD, ROP, IVH, PVL, NEC ), mortality were of no significant difference among three groups ( P > 0. 05 ) . Conclusions High dose caffeine therapy for apnea of prematurity is more effective in decreasing incidence of extubation failure and apnea, as well as decreasing duration of apnea and oxygen therapy. Tachycardia is the only adverse effect of high dose caffeine therapy discovered by this study.