BACKGROUND: Malignant disorders in childhood are life-threatening conditions, and issues regarding the children's health-related quality of life (HRQOL) are crucial in paediatric oncology. The overall aim of this study was to explore HRQOL in children with cancer in two countries, Argentina and Sweden, which have different cultural contexts. The specific aims were: to determine HRQOL by gender, age, diagnosis, treatment modality, time since diagnosis, and parental education/employment across cultures. Further aims were to assess the child/parent relationship in HRQOL and the influence of demographic variables in psychosocial and physical HRQOL in each country. METHODS: A cross-sectional study was performed in 2014, including 58 children (24 females, 34 males) and 62 parents/guardians. The instrument, the Pediatric Quality of Life Inventory™ (PedsQL™, generic, cancer and fatigue modules), and medical records were used. The response rate was 97%. RESULTS: The mean age of the children was 8.67 years (SD 5.1, range 2-18 years) and the mean time on treatment was 10.7 months (SD 8.7, range 1-30 months). The most common diagnosis was leukaemia (57%). In Argentina, in comparison with Sweden, a higher estimation of generic HRQOL was reported among adolescents (p = 0.022) and more cancer-related problems among school-age children (p < 0.0001). Children and parents in both countries confirmed the major problem with fatigue and multimodality therapy regimes, but lower levels of fatigue were reported in Argentina. Adolescents and children with solid tumours appeared as vulnerable groups. In Sweden, children whose mothers had post-secondary education reported less cancer-related problems (p = 0.031). Good relationships were found between child/parent reports in Argentina regarding the fatigue module (p = 0.034) and physical subscale (p = 0.014), and in Sweden regarding generic health (p = 0.004), including psychosocial (p = 0.006) and physical subscales (p = 0.042), and cancer (p = 0.001), and fatigue (p < 0.0001) modules. In Sweden, psychosocial health (OR 7.5; p = 0.007) and physical health (OR 6.2; p = 0.011) were positively influenced by being a school-age child. CONCLUSIONS: Fatigue is as a major problem across cultures. Still, being in school facilitates recovery. Good relationships in psychosocial HRQOL highlight professional challenges regarding severe issues and open communication, and the need of performing comparative studies of HRQOL of children with cancer from different cultural backgrounds.