Apnea of prematurity is associated with increased risk of death or disability in very preterm infants. An International randomized placebo-controlled study, the Caffeine for Apnea of Prematurity trial, demonstrated that neonatal caffeine therapy reduced rates of neonatal morbidities, including cerebral palsy and cognitive delay, and improved survival in infants at 18 to 21 months of age. It is unclear whether the beneficial effects of caffeine are maintained in older infants. Further, there is also concern that neonatal caffeine exposure may cause long-term harm. This 5-year follow-up study of Caffeine for Apnea of Prematurity was designed to determine the possible lasting benefits of caffeine therapy or newly apparent risks at 5 years of age. Of the 2006 participants from 35 clinical centers in the initial trial conducted between 1999 and 2004, 1932 (96.3%) from 31 clinical centers were enrolled in this follow-up study between 2005 and 2011. The primary study outcome measures were a composite of death or survival before a corrected age of 5 years with one or more of the following: motor impairment (cerebral palsy), cognitive impairment (delay), behavior problems, poor general health, severe hearing loss, and bilateral blindness. Motor impairment was defined as a Gross Motor Function Classification System level of 3 to 5 and cognitive impairment as a Full Scale Intelligence Quotient <70. The odds ratio for the comparisons was adjusted for center. There was no statistically significant difference for the combined outcome of death or disability at 5 years of age between the 833 children assigned to caffeine and the 807 children assigned to placebo (21.1% vs. 24.8%); the adjusted odds ratio was 0.82, with a 95% confidence interval of 0.65–1.03 (P = 0.09). No significant difference was found between the 2 groups for rates of death, motor impairment, behavior problems, poor general health, deafness, and blindness. The rates of cognitive impairment were lower at 5 years than at 18 months and similar in the caffeine and placebo groups (4.9% vs. 5.1%; adjusted odds ratio, 0.97; 95% confidence interval, 0.61–1.55 [P = 0.89]). These findings show that the benefits of neonatal caffeine therapy on the rate of survival without disability at 18 months in very preterm infants were attenuated at 5 years of age.