This study examines psycho-social impact of HIV and quality of life of 646 HIV-infected persons from a major government sexually transmitted disease (STD) clinic in South India. In this cross-sectional study, data was collected using interview schedule and scales. Nearly 70% had problems in parenting their children after acquiring the infection. Most (88%) of the respondents reported of seeking help from their family members, relatives or close friends at the time of their illness. Among the four categories of stigma, most of them (96%) reported perceived stigma whereas actual stigma was mentioned by only 33%. All four categories of stigma were experienced on a higher proportion by females than males (p<0.05). Each type of stigma was significantly associated with each domain of quality of life of the respondents (p<0.005). Respondents who reported of actual stigma (33%) had significantly good quality of life in their physical domain (49%), psychological domain (48%) and environmental domain (44%). Multivariate analysis showed that gender and marital status had significant association with quality of life. The findings of the study underscore the need for enabling environment through "human force" to uplift their social status and to have a better quality of life.