Corticosteroids, intramuscular vitamin A and caffeine reduce the risk of bronchopulmonary dysplasia (BPD) in very-low-birth-weight infants. We compared the size of the beneficial drug effects on BPD and evaluated long-term drug safety by estimating the number needed to treat (NNT) and the number needed to harm (NNH) for the outcome of cerebral palsy (CP). When given prophylactically during the first 4 days of life, corticosteroids increase the risk of CP (NNH 22; 95% CI: 12–133). When prescribed between days 7 and 14, corticosteroids reduce the 28-day mortality rate in addition to reducing BPD. Their effect on CP remains uncertain: the limited data available are consistent with a best-case scenario (NNT 15) and a worst-case scenario (NNH 14). Although repeated intramuscular injections of vitamin A during the 1st month of life reduce BPD (NNT 12; 95% CI: 6–94), estimates for CP range from an NNT of 11 to an NNH of 33. Early use of caffeine reduces both BPD and CP. The NNT for BPD is 10 (95% CI: 7–16), while the NNT for CP is 34 (95% CI: 20–132). We conclude that caffeine is the drug of choice for the prevention of BPD in very-low-birth-weight infants. Corticosteroids should be avoided during the first few days of life. However, when given during the 2nd week of life to infants at high risk of BPD corticosteroids may have important short- and long-term benefits. These should be urgently confirmed or refuted in well-designed controlled trials.