BackgroundThis study aimed to compare the quality of life (QoL) reported by childhood cancer survivors (CCS) drawn from a cohort of the German Childhood Cancer Registry with a representative general population sample and, within CCS, to test associations between QoL and health behavior, health risk factors, and physical illness.MethodsCCS (N= 633, age at diagnosisM= 6.34 (SD= 4.38), age at medical assessmentM= 34.92 (SD= 5.70)) and a general population sample (age-aligned;N= 975) filled out the EORTC QLQ-C30. Comparisons were performed using General linear models (GLMs) (fixed effects: sex/gender, group (CCS vs. general population); covariates: age, education level). CCS underwent an extensive medical assessment (mean time from diagnosis to assessment was 28.07 (SD= 3.21) years) including an objective diagnosis of health risk factors and physical illnesses (e.g., diabetes and cardiovascular disease). Within CCS, we tested associations between QoL and sociodemographic characteristics, health behavior, health risk factors, and physical illness.ResultsCCS, especially female CCS, reported both worse functional QoL and higher symptom burden than the general population. Among CCS, better total QoL was related to younger age, higher level of education, being married, and engaging in active sports. Both health risk factors (dyslipidemia and physical inactivity) and manifest physical illnesses (cardiovascular disease) were associated with lower total QoL.ConclusionsIn all domains, long-term CCS reported worse QoL than the comparison sample. The negative associations with risk factors and physical illnesses indicate an urgent need for long-term surveillance and health promotion.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12955-023-02153-7.