Background: Major life transitions (e.g., graduation from high school) are times when many changes occur in a person’s social and physical environment. Men and women likely experience aspects of these changes differently. As a result, health-related behaviors likely change at these times with possible differences in these changes by gender. Methods: Gender differences in the performance of chronic disease risk-related behaviors (fruit, juice, and vegetable intake; physical activity; tobacco and alcohol use; and sexual practices) through the transition out of high school (HS) were assessed in a secondary analysis of a nationally representative sample from the 1992 National Health Interview Survey–Youth Risk Behavior Survey. The survey was completed by 5881 young people aged 14 to 21 years. Regression discontinuity analysis with piecewise regression was performed. Results: Statistically significant gender by transition effects were obtained for exercise/physical activity (decreases at the transition point for males), snuff use (decrease for females in HS), binge drinking and number of days drinking alcohol (increases for males at the transition point), and use of alcohol or drugs before sexual intercourse (decrease for females post HS). Fruit intake decreased for males and females and daily and heavy cigarette smoking increased during the HS years. Effect sizes were small but promising, given that the data set was not designed to test this hypothesis. Conclusion: These data offer evidence of differences by gender in chronic disease risk behaviors through the HS transition. Longitudinal studies are needed to assess the true nature of these differences, the tracking of these risk behaviors and their personal, social, and environmental determinants, including gender-specific determinants, that may explain these changes and inform future intervention development.