We used a Stress and Coping model to examine the association of dispositional mindfulness, defined as the tendency to intentionally bring nonjudgmental attention and awareness to one's experience in the present moment, with psychological and physical health in adults with HIV. Data were collected at baseline of a randomized controlled trial of Mindfulness-Based Stress Reduction (MBSR). Four facets of mindfulness (acting with attention/awareness, nonjudging of inner experience, observing, and describing) were examined as correlates of appraisal, positive and negative affect, coping, and indicators of psychological well-being and physical health. We found that mindfulness was inversely related to depression, stress appraisal, and negative affect, and positively related to positive affect. Mindfulness was also inversely related to escape/avoidance and self-blame forms of coping. Mediational analyses indicate that perceived stress and negative affect were the most consistent mediators of the association of mindfulness and psychological well-being. The findings from this paper contribute to a growing understanding of the potential adaptive role of mindfulness in people living with the stress of serious illness.