We have compared intravenous magnesium sulphate vs. inhaled nitric oxide in the therapy of moderate persistent pulmonary hypertension of the neonate. A retrospective collection of clinical data from 58 neonates was carried out in six neonatal intensive care units of Southern Italy sharing the same operational protocols. In our setting, both drugs were effective in treating moderate persistent pulmonary hypertension of the neonate but nitric oxide (NO) treatment resulted in much faster amelioration of oxygenation index, taken as a marker of the underlying condition. No significant difference was recorded in immediate or long-term complications. We conclude that, wherever NO facilities are not readily available, magnesium sulphate is a safe and cheaper alternative for first-line treatment of moderate persistent pulmonary hypertension of the neonate.