Frequent substance use has a strong association with poor mental health. The relationship between infrequent substance use and mental health is less clear. The present study investigated this relationship in a large group (n = 2118) of 12-19-year-olds from Alberta, Canada. Results indicated that adolescents who used tobacco or alcohol once a month or less tended to have equivalent mental health status to abstainers. Using cannabis 3-5 times/year or less had no adverse mental health associations. However, poorer mental health was associated with single time use of hallucinogens or other drugs. In general, substance usage tended to have more negative mental health associations for younger compared to older adolescents.