AIM: Illicit substance use during pregnancy is associated with an increased rate of perinatal complications. Our study examines if outcome of infants of substance-using mothers (ISMs) in the neonatal intensive care unit (NICU) setting is similar to unexposed infants (controls). METHODS: A prospective state-wide NICU study comparing ISMs to control infants admitted to 10 NICUs during a 3-years period (2001-2003). An ISM was defined as an infant whose mother admitted to or was documented to have used substances of dependency (illicit or otherwise) during this pregnancy. RESULTS: There was a preponderance towards prematurity with ISMs comprising 5.1% (n=310) of 6120 high risk infants (6.2% (n=165) <32 weeks gestation and 6.8% (n=39) of 22-26 weeks gestation). More ISMs were outborn and had significantly lower mortality rate, particularly in the <32 week gestation subgroup (adjusted OR 0.517 95% CI 0.277-0.962, P<0.037). ISMs also demonstrated a non-significant trend towards an increased risk of neonatal morbidities. The pattern of rural and urban substance use was different, with a higher incidence of opiate use (49.3% vs. 26.9%, P<0.001) in urban areas. Most opiate using mothers (85.6%), irrespective of rural or urban residence, were enrolled in methadone programmes. ISMs had a higher incidence of antepartum haemorrhage and chorioamnionitis and fewer were given antenatal steroids. CONCLUSION: ISMs are common in the high-risk NICU population. Further studies are needed to confirm the lower mortality rate and long-term outcomes in these infants.