BACKGROUND: Caregivers of people with chronic conditions are more likely than non-caregivers to have depression and emotional problems. Few studies have examined the effectiveness of mindfulness-based stress reduction (MBSR) in improving their mental well-being. METHODS: Caregivers of persons with chronic conditions who scored 7 or above in the Caregiver Strain Index were randomly assigned to the 8-week MBSR group (n = 70) or the self-help control group (n = 71). Validated instruments were used to assess the changes in depressive and anxiety symptoms, quality of life, self-efficacy, self-compassion and mindfulness. Assessments were conducted at baseline, post-intervention and at the 3-month follow-up. RESULTS: Compared to the participants in the control group, participants in the MBSR group had a significantly greater decrease in depressive symptoms at post-intervention and at 3 months post-intervention (p < 0.01). The improvement in state anxiety symptoms was significantly greater among participants in the MBSR group than those of the control group at post-intervention (p = 0.007), although this difference was not statistically significant at 3 months post-intervention (p = 0.084). There was also a statistically significant larger increase in self-efficacy (controlling negative thoughts; p = 0.041) and mindfulness (p = 0.001) among participants in the MBSR group at the 3-month follow-up compared to the participants in the control group. No statistically significant group effects (MBSR vs. control) were found in perceived stress, quality of life or self-compassion. CONCLUSIONS: MBSR appears to be a feasible and acceptable intervention to improve mental health among family caregivers with significant care burden, although further studies that include an active control group are needed to make the findings more conclusive.