Despite the recent growth of mindfulness research worldwide, there remains little research examining the application of mindfulness-based interventions in resource-limited, international settings. This study examined the application of Mindfulness-Based Stress Reduction (MBSR) for HIV-infected individuals in South Africa, where rates of HIV are highest in the world. Mixed methods were used to examine the following over a three-month follow-up: (1) feasibility, acceptability, and preliminary adaptation of MBSR for this new context; and (2) effects of MBSR on immune functioning, self-reported mindfulness (MAAS, FFMQ), depression, anxiety, and stress (DASS-21). Ten individuals initiated MBSR, and seven completed all eight sessions. Results indicated medium effect size improvements in immune functioning (CD4 count and T cell count; d = .5) through the three-month follow-up, though the small sample size limited power to detect a statistically significant effect. From baseline to post-treatment, improvements in “Observing” and “Non-reactivity” (FFMQ) approached statistical significance with large effect sizes (observing: d = 1.5; p = .08; non-reactivity: d = .7; p = .07). There were no statistically significant changes in depression, anxiety, or stress throughout the study period. Primary areas for adaptation of MBSR included emphasis on informal practice, ways to create “space” without much privacy, and ways to concretize the concepts and definitions of mindfulness. Feedback from participants can shape future adaptations to MBSR for this and similar populations. Findings provide preliminary evidence regarding the implementation of MBSR for individuals living with HIV in South Africa. A future randomized clinical trial with a larger sample size is warranted.