Objective: To investigate the effects of the association of inhaled nitric oxide (iNO) and oxidant drugs (acetaminophen, phytomenadione, and EMLA cream) on methemoglobinemia during the neonatal period. Design: Prospective, randomized, experimental study. Setting: University Experimental Pharmacology laboratory. Subjects: Sixty newborn piglets weighing 1.5-2.0 Kg. Interventions: Twelve groups of five piglets were anaesthetized, mechanically ventilated, and studied for 3 hrs. Eight groups received iNO (40 ppm or 80 ppm) alone or in association with a single intravenous dose of acetaminophen (120 mg/kg propacetamol), phytomenadione (5 mg vitamin K1) or EMLA cream (2.5 g) applied to the ventral lower abdomen for 3 hrs. Three other groups received, respectively, acetaminophen, phytomenadione, or EMLA cream without iNO. The last group (control group) received neither drugs nor iNO. Measurements and Main Results: Methemoglobinemia was measured before the beginning of each experiment, 30 mins later, and every hour for 3 hrs. There was no significant difference in methemoglobinemia at any time between groups receiving acetaminophen (0.90% ± 0.12%), phytomenadione (0.88% ± 0.11%), or EMLA cream alone (0.97% ± 0.11%) and the control group (0.92% ± 0.12%). At 3 hrs, methemoglobinemia was slightly but significantly increased in group receiving iNO alone (1.04% ± 0.17% at 40 ppm iNO and 1.14% ± 0.16% at 80 ppm iNO; p