Research into the equivalence of Western and Japanese conceptualizations of health-related quality of life (HR-QOL) is scarce. We used the Western (European Organization for Research and Treatment of Cancer, EORTC-QLQ-C30) and the Japanese (HRQoL-20) questionnaire in order to analyze the conceptual similarity of HR-QOL factors, and the associations between specific symptom items with overall HR-QOL in Japanese (n = 265) and Dutch (n = 174) patients with various types of cancer. Both populations completed both instruments. In both patient groups, the overall health scale of the EORTC-QLQ-C30 correlated highly (r = 0.59; p < 0.001) with the HRQOL-20 composite average score, indicating substantial conceptual comparability. Relationships between all EORTC-QLQ-C30 symptom items with HR-QOL were examined by ranking their correlations with the two overall measures of HR-QOL. Comparable patterns in the Japanese and Dutch samples were observed. The results suggest a considerable conceptual equivalence of HR-QOL in Japanese and Dutch cancer patients, and indicate a satisfactory structural and cross-cultural equivalence for the EORTC-QLQ-C30 with regard to items measuring functioning and specific symptoms. Longitudinal studies are needed to examine the impact of specific symptoms on general quality of life.