Health-related quality of life (HRQL) is a good indicator to monitor and evaluate healthcare services for adults with HIV/AIDS. This study described HRQL of adults with HIV and its determinants, and compared it with HRQL for the general population. A cross-sectional study with a national multistage sampling of households with and without HIV-positive people was conducted in 2008. Six provinces were purposively selected to represent areas of the country and progressions of HIV epidemics. Households were sampled with probability-proportional-to-size, following the selection of rural and urban districts. A total of 820 HIV-positive and HIV-negative adults (mean age: 32.5; 38.7% female) were interviewed. Among 400 HIV-positive people, 52.3% had a history of injecting drugs, and 56.3% were at AIDS stage and receiving antiretroviral treatment (ART). HRQL was measured using the EuroQOL five-dimension questionnaire (EQ-5D). Multiple regression models were purposefully constructed to examine the determinants of HRQL. The EQ-5D index and visual analog scale (VAS) score in less advanced HIV people (0.90, 69.3) and AIDS patients (0.88, 65.2) were significantly lower than those of the general population (0.96, 81.6) (p<0.001). The frequency of reported problems across EQ-5D dimensions in the HIV population (2.4-30.9%) was significantly higher than in the general population (0.7-12.1%). Compared to ART patients, those at earlier HIV stages reported having problems at similar proportions across four HRQL dimensions, except pain/discomfort, where ART patients had a significantly higher proportion. Injecting drug users taking ART perceived lower HRQL score than non-injecting drug users. Multiple regression determined that joblessness (p<0.01) and inaccessibility to health services (p<0.05) were associated with lower HRQL. In addition, involvements in self-help groups significantly improved HRQL among HIV-positive participants (p<0.05). The findings highlight the need to improve the health service referral system and enhance psychological and social supports for patients in early stages of HIV infection in Vietnam.