Although the relationship between job stress and depressive symptoms has been well documented among workers in large scale enterprises, the situation in small-and medium-scale enterprises (SMEs) is not fully understood. Objectives: To clarify the factors associated with depressive symptoms in SMEs in Japan. Methods: 1,516 male and 738 female Japanese workers at SMEs were surveyed using a self-administered questionnaire. We applied hierarchical multiple linear regression with depressive symptoms (Center for Epidemiologic Studies Depressive Symptoms Scale) as the dependent variable, and (1) Individual, (2) Lifestyle, (3) Job stressors, and (4) SME unique factors as independent variables entered in 4 steps. Analyses were stratified by sex due to large differences in stress scores and demographic variables. Results: Perceived lack of understanding from others with regard to health was the strongest factor associated with increased depressive symptoms (BETA=0.29 in males and 0.28 in females). Higher intragroup conflict (BETA=0.15 in males and 0.09 in females), perceived job future ambiguity (BETA=0.09 in males and 0.11 in females), higher quantitative workload (BETA=0.06 in males and 0.10 in females), and being an employer or a member of the employer's family (BETA=0.06 in males and 0.10 in females) were additional factors associated with high depressive symptoms. Economic concern, being single, cigarette smoking, shorter sleep duration, and skill underutilization were male specific, while younger age and lower social support at work were female specific factors significantly associated with increased depressive symptoms. Conclusions: These data suggest that poor mental health may be prevented by creating a workplace climate which focuses on the high value of the health of fellow workers. (J Occup Health 2009; 51: 26-37)