In light of the known associations between stress, negative affect, and relapse, mindfulness strategies hold promise as a means of reducing relapse susceptibility. In a pilot randomized clinical trial, we evaluated the effects of Mindfulness-Based Relapse Prevention (MBRP), relative to a health education control condition (HE) among stimulant-dependent adults receiving contingency management. All participants received a 12-week contingency management (CM) intervention. Following a 4-week CM-only lead in phase, participants were randomly assigned to concurrently receive MBRP (n = 31) or HE (n = 32). The primary outcomes were stimulant use, measured by urine drug screens weekly during the intervention and at 1 month post-treatment, negative affect, measured by the Beck Depression Inventory and Beck Anxiety Inventory, and psychiatric severity, measured by the Addiction Severity Index. Medium effect sizes favoring MBRP were observed for negative affect and overall psychiatric severity outcomes. Depression severity changed differentially over time as a function of group, with MBRP participants reporting greater reductions through follow-up (p = 0.03; effect size = 0.58). Likewise, the MBRP group evidenced greater declines in psychiatric severity (p = 0.01; effect size = 0.61 at follow-up). Among those with depressive and anxiety disorders, MBRP was associated with lower odds of stimulant use relative to the control condition (odds ratio (OR) = 0.78, p = 0.03 and OR = 0.68, p = 0.04). MBRP effectively reduces negative affect and psychiatric impairment, and is particularly effective in reducing stimulant use among stimulant-dependent adults with mood and anxiety disorders.