Objective - To quantify various forms of poly-drug use among the French population, as well as the main factors associated with it. Methods - Using data from a general population survey focusing in part on drug use, the 2005 Health Barometer, poly-drug use was assessed using two indicators: regular poly-drug use of at least two substances among alcohol, tobacco, and cannabis; and the cumulative use, over the course of the year, of at least two illicit drugs other than cannabis, without it being possible to confirm that these were concurrent uses. Results - Regular poly-substance use of alcohol, tobacco, or cannabis affected 8.3% of the population. Those aged 20–24 were one of the age groups with the highest rates of tobacco and cannabis use, at 11.6%. Regular poly-substance use of all three substances was rare: less than 1% of individuals aged 15 to 64; it was highest among those aged 20–29, at less than 2% of that age group. The primary association was between alcohol and tobacco starting at age 35. Poly-substance use involving cannabis was rare among those over 34 years of age. There was a strong link between cannabis use and the use of other illicit psychoactive substances. Lifetime use of illicit psychoactive substances other than cannabis affected 10.0% of those aged 15–34; for use within the past year, the figure was 2.3%. Factors associated with these practices included unemployment, being male, and being young, whereas enrollment in higher education appeared to be a factor that distanced young adults from various forms of poly-substance use. Discussion - Situations of poly-substance use often result in risk-taking or vulnerability, justifying particular attention to these practices. General population surveys do not cover the most vulnerable and marginalized populations and do not allow for a description of problematic forms of poly-substance use. They provide useful contextual information for assessing the prevalence of the most common forms of poly-substance use in the population and evaluating their likely health and social impacts.