Background: Hemophilia A can seriously affect the HRQoL of children and adolescents. The aim of this systematic review was to identify studies that have reported HRQoL of this patient population and to assess its relation to effective prophylactic treatment. Methods: Randomized or observational clinical studies published in English, Portuguese, or Spanish that recruited a minimum of 30 patients aged < 18 years with non-inhibitor hemophilia A and reported on the results of HRQoL assessment were included. We excluded reports with no primary data reporting. We searched MEDLINE, EMBASE, CENTRAL and LILACS databases from 2010 to 2021. Risk of bias was assessed with the Newcastle-Ottawa Scale. Results are presented as a meta-regression of the proportion of patients under prophylactic treatment on the outcome variable HRQoL as measured with the Haemo-QoL questionnaire (higher scores indicating worse HRQOL). Funded by Roche Pharmaceutical. PROSPERO registration CRD42021235453. Results: The initial search yielded 2220 records. After title and abstract screening, 98 studies were retrieved for full text reading, of which 14 studies (778 patients from 12 countries) met the inclusion criteria for the meta-regression analysis. The proportion of patients on prophylactic treatment ranged from 0% to 100% of patients on a prophylactic regimen with regular administration of FVIII (11 studies), turoctocog alfa (two studies), or emicizumab (one study). There was a significant negative association between higher Haemo-QoL scores (worse HRQOL) and the proportion of patients receiving continuous prophylactic treatment (mixed-effects model, Tau²=42.7323 (SE=23.9699), I²=94.67%, H²=18.76%, R²=79.34%, y=55.4442-37.4145*x). Three out of the six studies with the highest HRQoL scores (mean total Haemo-QoL score < 30) were treated with extended half-life hemostatic agents. Discussion: Most of the observed overall heterogeneity was explained by the range of prophylactic treatment reported in diverse settings. A higher proportion of children with hemophilia A on prophylactic treatment is associated with better HRQOL.