BACKGROUND: The efficacy of the mindfulness-based stress management program for maintaining a better mental state has not been examined among working populations. We aimed to explore the effectiveness of the brief mindfulness-based stress management program for hospital nurses. METHODS: In a multi-center randomized trial, 80 junior nurses working in hospitals were randomly allocated either to the brief mindfulness-based stress management program or psychoeducation using a leaflet. The program consisted of four 30 min individual sessions conducted by trained senior nurses using a detailed manual. The primary outcome was the total score of the Hospital Anxiety and Depression Scale (HADS) at week 26. Secondary outcomes included presence of a major depressive episode; severity of depression, anxiety, insomnia, burnout, and presenteeism; utility scores; and adverse events up to 52 weeks. RESULTS: The mean HADS score of all the participants at baseline was 7.2. At 26 weeks, adjusted mean scores on the HADS score were 7.2 (95% confidence intervals: 5.9, 8. 5) in the program group and 6.0 (4.8, 7.2) in the leaflet group, respectively. The coefficient of the group by time interaction was not statistically significant at -1.41 (-3.35, 0.54; P = 0.156). No significant superiority or inferiority was observed on the other outcomes. LIMITATIONS: We did not manage to recruit the number of participants we initially set out, although our post-hoc analyses showed that this did not lead to changes in our conclusions. CONCLUSIONS: The additive value of the brief mindfulness-based stress management program was not confirmed in mental state and self-evaluated work efficiency.