This study examined the association of spirituality and health-related quality of life among 226 HIV-positive men. Two measures of spirituality were used: the Spiritual Growth subscale from the Health-Promoting Lifestyle Profile II (S. N. Walker, K. R. Sechrist, & N. J. Pender, 1987) and the Spirituality subscale of the HIV Coping Instrument (L. Moneyham, A. Demi, Y. Mizuno, R. Sowell, & J. Guillory, 1998). Health related quality of life was measured with the HIV Cost and Services Utilization Study (R. D. Hays et al., 1998). Spiritual coping (i.e., relying on religion-based coping techniques) was not associated with health-related quality of life at baseline or 12-month follow-up. Spiritual growth (i.e., existential feelings of connection with a force greater than oneself) improved some aspects of mental and emotional well-being but did not affect physical functioning or pain management. (Contains 3 tables.)