This study sought to examine gender-based differences in the quality of life of men and women living with HIV in South India in the era prior to greater access to antiretroviral therapy. The participants in this prospective longitudinal study consisted of 215 men and 141 women who were administered a quality of life (QOL) instrument comprising five scales: physical well-being, psychosocial well-being, sexual well-being, satisfaction with health care, and strength of partner relationship. Interviews were conducted at enrollment and at 6 months in clinical care. Men and women reported similar scores in physical well-being, satisfaction with health care, and relationship with partner from the period prior to care, at enrollment, and at 6 months. Women scored significantly lower than men in psychosocial well-being from the period prior to care, at enrollment, and at 6 months (p < 0.05); women reported significantly higher levels of partner satisfaction at 6 months (p < 0.05). In light of the increasing feminization of the HIV epidemic in India, greater emphasis should be placed on examining the long-term experiences of Indian women living with HIV/AIDS, particularly their psychosocial well-being.