Introduction: Quality of life (QoL) is important for people living with HIV/AIDS, particularly as the disease progresses. This study evaluated the QoL of people living with HIV/AIDS (PLWHA), as well as its predictors, in one of the most impoverished regions of Brazil. Methods: This cross-sectional study was conducted with patients older than 18 years with HIV/AIDS from two specialized HIV/AIDS care centers in the city of Montes Claros between 2013 and 2014. Sample size was calculated considering the estimates of mean scores for various dimensions of the European Portuguese version of the World Health's Organization Quality of Life Instrument in HIV Infection (WHOQOL-HIV Bref). The following parameters were adopted: CI of 95%, estimated mean scores for QoL equal to 15, estimated variance for QoL scores equal to 16, and 5% relative margin of error. An increase of 20% was established to compensate for possible non-responses or losses, and correcting any design effect, adopting a deff equal to 2.0. Calculations revealed the need to interview at least 221 patients. Therefore, 226 patients living with HIV/AIDS were randomly selected. Results: A total of 226 patients with mean age 43.7 years were evaluated: 51.8% men, 51.8% unemployed, 51.8% with low schooling level, 89.8% used antiretrovirals, and 43.3% experienced depression. Despite this, data indicated that 65% self-assessed their QoL as good and very good. Low QoL was associated with sociodemographic variables and some clinical variables. Conclusions: Depression was the main predictor of low QoL in all domains evaluated.