Background Sickle cell disease (SCD) is a chronic hematologic disease associated with increased morbidity and mortality. Hemoglobinopathies are the most prevalent genetic disease globally, and SCD is estimated to affect 0.7% of Ugandan. The disease may adversely impact on the quality of life of sickle cell patients. This study aimed to evaluate the health related quality of life (HRoL) of adolescents with SCD. Methods This was a mixed-methods study of adolescents with sickle cell disease and their caretakers living in Kampala city, Uganda. All children aged 8–17 years with homozygous sickle cell disease attending the sickle cell clinic at Mulago Hospital during the study period were included in this study. Participants completed the PedsQL™ generic core scales parent-proxy and child self-report questionnaire during a routine clinic visit. HRQoL was the primary outcome measured. Socio-demographics and disease related data were obtained through personal interview with caretakers and reviewing patients’ medical records. Mean scores were used for HRQoL and linear regression for associated factors. Results