There is growing evidence supporting the notion that exposure to air pollution can contribute to cognitive and psychiatric disorders, including depression and suicide. Given the relationship between exposure to acute stressors and substance abuse, the present study assessed the association between exposure to ambient air pollution and emergency department (ED) visits for alcohol and drug abuse. ED visit data selected according to International Classification of Disease (ICD-9) coding 303 (alcohol dependence syndromes) and 305 (non-dependent abuse of drugs) were collected in five hospitals in Edmonton, Canada. A time-stratified case crossover design was used. Conditional logistic regression was applied to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Season, temperature, and relative humidity were adjusted for using natural splines. Results are reported for an increase in pollutant concentrations equivalent to one interquartile range (IQR). Statistically significant positive associations with substance abuse were observed for CO, NO2 and particulate matter with an aerodynamic diameter less than 10 μm (PM10) and 2.5 μm (PM2.5). The strongest results were obtained in the cold period (October-March) for 1-day lagged CO (OR = 1.03, 95% CI: 1.01, 1.05, IQR = 0.4 ppm) and NO2 (OR = 1.04, 95% CI: 1.01, 1.07, IQR = 12.8 ppb); ORs were also significant for CO and NO2 with lags of 2 to 6 days and 2 to 7 days, respectively. The study suggests that, even at low levels, increases in ambient CO, NO2, and PMs are associated with increased hospital admissions for substance abuse, possibly as a result of impacts of air quality on mental health or depression.