Background: Few studies, and none in Canada, have examined the relation between maternal smoking, alcohol consumption and drug dependence during pregnancy and early neonatal morbidity. Methods: We analyzed records of singleton live births in Alberta, Canada. Markers of neonatal morbidity were Apgar scores (<7 at 5 minutes postpartum) and resuscitation measures (2001-2005, N=191,686), and neonatal intensive care unit (NICU) admissions (2002-2005, N=154,924). Logistic regression was used to estimate odds ratios (ORs) for self-reported substance use and maternal health before conception, adjusting for maternal age, parity, year and fetal gender. Univariate ORs and population-attributable fractions were computed with and without correction for under-reporting of substance use. Results: Maternal smoking during pregnancy was the most prevalent risk factor, affecting 20% of mothers by self-report, with the figure being possibly twice as high once corrected for under-reporting. Smoking (ORs 1.2), alcohol consumption (ORs 1.2-1.5) and drug dependence (ORs 1.7-2) by the mother during pregnancy were associated with increased risk for each of the markers of early neonatal morbidity (p<0.05, after correcting for covariates). Eliminating the most common among these risk factors, maternal smoking, would prevent 10-15% of each of the three neonatal morbidity markers. Other recorded factors related to mother's pre-conception health, despite some strong associations, were responsible for only a small proportion of cases. Discussion: We conclude that in preventing early neonatal morbidity among singleton births in Alberta, control of maternal smoking, the most common of the potentially modifiable risk factors, remains an important goal.