ABSTRACT We examined the association between five-factor personality domains and facets and spirituality/religiousness as well as their joint association with mental health in a diverse sample of people living with HIV (n=112, age range 18–66). Spirituality/religiousness showed stronger associations with Conscientiousness, Openness, and Agreeableness than with Neuroticism and Extraversion. Both personality traits and spirituality/religiousness were significantly linked to mental health, even after controlling for individual differences in demographic measures and disease status. Personality traits explained unique variance in mental health above spirituality and religiousness. Further, aspects of spirituality and religiousness were found to mediate some of the links between personality and mental health in this patient sample. These findings suggest that underlying personality traits contribute to the beneficial effects of spirituality/religiousness among vulnerable populations.