Few studies have assessed differences in the prevalence of and economic burden attributable to tobacco smoking, excess weight, physical inactivity, and alcohol use by gender. This article examines these gender differences in Canadians between the ages of 30 and 64 years. It also estimates the potential cost avoidance if the prevalence of the four risk factors (RFs) were reduced modestly in males. Data on the prevalence of the RFs and the relative risk of disease associated with each of the RFs were combined to calculate population-attributable fractions. A prevalence-based cost-of-illness approach was used to estimate the economic burden associated with the four RFs. Middle-aged Canadian males are more likely to smoke tobacco (26.4% vs. 20.2%), consume hazardous or harmful levels of alcohol (14.6% vs. 8.2%), and have excess weight (65.6% vs. 47.1%) than middle-aged Canadian females, resulting in an annual economic burden that is 27% higher in males than females. No significant differences were observed in the proportion of males who are physically inactive (48.4% vs. 49.4%). Modelling only a 1% annual relative reduction each year through to 2036 would result in a cumulative cost avoidance between 2013 and 2036 of $50.7 billion. The differences in RF prevalence between middle-aged males and females have an important effect on the population’s economic burden. A modest annual reduction in the four RFs in males can significantly affect population health and the economy over time.