Background: Health-related quality of life (HRQoL) has become a major concern in the field of children’s health research. We assessed HRQoL among Iranian children and adolescents according to the socioeconomic status (SES) of their living region.Methods: Via multistage cluster sampling from rural and urban school students aged 6 to 18 years, this nationwide study was conducted from 2011 to 2012. HRQoL was assessed using the adolescent core version of the Pediatric Quality of Life questionnaire. Through survey data analysis methods, the data were compared according to the SES of the living region, sex, and the living area.Results: Overall, 23043 students participated in the survey (participation rate=92.2%). The mean age of the participants was 12.55±3.31 years. Boys accounted for 50.8% of the study population, and 73.4% were from urban areas. At national level, the mean of the HRQoL total score was 81.7 (95% CI: 81.3 to 82.1) with a mean of 83.5 (95% CI: 83.0 to 84.1) for the boys and 79.8 (95% CI: 79.1 to 80.5) for the girls. The highest and the lowest scores, respectively, belonged to social functioning (90.0 [95% CI: 89.7 to 90.3]) and emotional functioning (78.2 [95% CI: 77.7 to 78.7]). The highest total HRQoL score belonged to the second highest SES region of the country (mean=83.1; 95% CI: 82.5 to 83.7). The association between total HRQoL and the score of all the subscales and SES in the living area was statistically significant (P<0.001).Conclusion: The results of the present study showed that in the children and adolescents, SES was associated with HRQoL. Accordingly, HRQoL and the related SES differences should be considered one of the priorities in health research and health policy.