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.