Background: Studies on health-related quality of life (HRQoL) inequalities according to sexual orientation are scarce. The aim of this study was to assess HRQoL inequalities between lesbian, gay, and bisexual (LGB) people and heterosexuals in the 2011 Barcelona population, to describe the extent to which sociodemographic characteristics, health-related behaviors, and chronic conditions could explain such inequalities, and to understand if they are sexual orientation inequities. Methods: In the 2011 Barcelona Health Interview Survey 3277 adults answered the EQ-5D, which measures five dimensions of HRQoL summarized into a single utility index (1 = perfect health, 0 = death). To assess HRQoL differences by sexual orientation we constructed Tobit models for the EQ-5D index, and Poisson regression models for the EQ-5D dimensions. In both cases, nested models were constructed to assess the mediator role of selected variables. Results: After adjusting by socio-demographic variables, the LGB group presented a significantly lower EQ-5D index than heterosexuals, and higher prevalence ratios of problems in physical EQ-5D dimensions among both genders: adjusted prevalence ratio (aPR) = 1.70 for mobility (p = 0.046) and 2.11 for usual activities (p = 0.019). Differences in mental dimensions were only observed among men: aPR = 3.15 for pain/discomfort (p = 0.003) and 2.49 for anxiety/depression (p = 0.030). All these differences by sexual orientation disappeared after adding chronic conditions and health-related behaviors in the models. Conclusion: The LGB population presented worse HRQoL than heterosexuals in the EQ-5D index and most dimensions. Chronic conditions, health-related behaviors and gender play a major role in explaining HRQoL differences by sexual orientation. These findings support the need of including sexual orientation into the global agenda of health inequities.