Background. Long-term unemployment is associated with poorer mental health. The aim of this study was to evaluate the effectiveness of a health promotion program using the train-the-trainer approach on health-related quality of life (HRQoL) and mental health of long-term unemployed persons. Methods. A prospective parallel-group study was conducted among 365 longterm unemployed persons. 287 participants (179 members of the intervention group IG and 108 members of the control group) were reassessed after three months. The intervention comprised both individual sessions based on Motivational Interviewing and participatory group sessions; no health promotion program was administered in the control group. The endpoints were HRQoL (SF-12), depression, and anxiety. The effect size of the change across time in the IG and CG was measured by Cohen's d. To assess the significance of group differences in the change across time, a random effects model was used. Results. Within three months HRQoL improved and anxiety and depression decreased significantly in the IG. A significant intervention effect was observed for anxiety (p = 0.012). Effect sizes in the IG were small to moderate in terms of Cohen's d (anxiety: d = −0.33; SF-12 mental: d = 0.31; depression: d = −0.25; SF-12 physical: d = 0.19). Conclusions. The health promotion program, based on a train-the-trainer approach, showed positive effects on HRQoL and mental health, especially anxiety, of long-term unemployed persons, a highly burdened target group where an improvement in mental health is a crucial prerequisite to social participation and successful reintegration into the job market