BACKGROUND: To analyze perceptions of health-related quality of life and associated factors in populations from the Manaus Metropolitan Region. METHODS: We conducted a population-based cross-sectional study from May to August 2015. Adults aged 18 years and older were selected using probabilistic three-phase cluster sampling and stratified by sex and age, based on official estimates. Quality of life data were collected using the European Quality of Life 5-Dimensions 3-Levels (EQ-5D-3L) along with socioeconomic, demographic, and health perception data. Utility scores were calculated using the Brazilian version of the EQ-5D-3L. Descriptive statistics were derived, and a multivariate Tobit regression model with correction for complex sampling was performed to identify the variables that influence utility levels. RESULTS: A total of 4001 participants were included. The average utility score was 0.886 (95% confidence interval [CI]: 0.881-0.890) with significant differences according to living area (the capital (0.882 ± 0.144) or inner cities (0.908 ± 0.122; p < 0.001)). The dimension for which the highest proportion of people reported moderate to severe problems was pain/discomfort (39%), followed by anxiety/depression (18%). Men had a higher quality of life than women (ß = 0.041, p < 0.001). Not working was a factor that increased quality of life compared with being formally employed (ß = 0.031, p = 0.037). The poorest people had a lower quality of life than the richest people (ß = -0.118, p < 0.001). Better health perceptions increased utility scores (p < 0.001), while being separated decreased the scores (ß = -0.052, p = 0.001). CONCLUSION: Health-related quality of life in the Manaus Metropolitan Region was high, as expected for the general population, and was higher among individuals who lived in the inner cities, men and those in higher social classes. Gender discrepancies and differences in quality of life between the capital and inner cities should be further investigated.