We examined the efficacy of a psycho-spiritual intervention of mantram repetition—a word or phrase with spiritual associations repeated silently throughout the day–on psychological distress (intrusive thoughts, stress, anxiety, anger, depression), quality of life enjoyment and satisfaction, and existential spiritual well-being in HIV-infected adults. Using a 2-group by 4-time repeated measures design, 93 participants were randomly assigned to mantram (n=46) or attention control group (n=47). Over time, the mantram group improved significantly more than the control group in reducing trait-anger and increasing spiritual faith and spiritual connectedness. Actual mantram practice measured by wrist counters was inversely associated with non-HIV related intrusive thoughts and positively associated with quality of life, total existential spiritual well-being, meaning/peace, and spiritual faith. Intent-to-treat findings suggest that a mantram group intervention and actual mantram practice each make unique contributions for managing psychological distress and enhancing existential spiritual well-being in adults living with HIV/AIDS.