Background Individuals with certain personal, family and job characteristics are at elevated risk of poor mental health. Yet, the respective role of obesity, smoking, alcohol abuse, low education, income, living and family conditions, and sociooccupational category in fatigue/insomnia (FI), nervousness (N) and frequent drug use for those disorders (DFI and DN) among men and women and in gender disparities are not well known. Methods We studied gender differences in FI, N, DFI, DN, and in their correlated, and whether the gender differences were mediated by individual and lifestyle factors among 3,450 active subjects aged 18–64, randomly selected from North-eastern France. Subjects completed a post-mailed questionnaire. Data were analyzed via adjusted odds ratio (ORa) computed with the logistic regression model. Results Women were more affected than men for FI (21.3 vs. 13.1%, OR adjusted for age ORa 1.80, 95% CI 1.50–2.16), DFI (11.6 vs. 7.1%, ORa 1.74, 1.38–2.21), N (14.7 vs. 9.9%, ORa 1.58, 1.28–1.94), and for DN (12.1 vs. 5.7%, ORa 2.29, 1.79–2.94). These differences were not mediated by the individual characteristics studied. Multivariate analysis showed that the risk patterns varied between the two sexes. Smoking was related to N in men as well as in women; alcohol abuse to DFI in men only; lack of family support to all outcome variables in men and women; low educational level to DFI in men only; low income to FI, N and DN in men and to FI and DN in women; being unmarried to DN in men; being divorced/separated to N and DN in women; being a manual worker to FI and being a farmer to DFI in men; and being a manual worker to DN and being an employee to FI in women (1.50 £ ORa £ 2.95). Conclusions Women suffered more from fatigue/insomnia and nervousness and used more drug for those disorders than men. Socio-demographic and lifestyle factors played significant roles among men and women but they did not explain the gender disparities