PURPOSE: To compare the variability and sample size requirements of the global quality-of-life (QOL) scores of the following three major QOL instruments: the Functional Assessment of Cancer Therapy-General (FACT-G), Functional Living Index-Cancer (FLIC), and European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 (EORTC QLQ-C30). PATIENTS AND METHODS: Cancer patients were randomly assigned to answer two of the three instruments using an incomplete block design (n = 1,268). The instruments were compared in terms of coefficient of variation, effect size in detecting a difference between patients with different performance status, and correlation coefficient between scores at baseline and follow-up. RESULTS: The FACT-G and FLIC had significantly smaller coefficients of variation than the EORTC QLQ-C30 (both P < .05). The FLIC also had significantly larger correlation coefficients between scores at baseline and follow-up than the EORTC QLQ-C30 (P < .05). The FACT-G and the FLIC had a larger effect size in a cross-sectional and longitudinal setting, respectively, than the EORTC QLQ-C30 in differentiating patients with different performance status (both P < .05). CONCLUSION: In some aspects, the FACT-G and FLIC global QOL scores had smaller variability and larger discriminative ability than the EORTC QLQ-C30. Further research using other criteria to compare the three instruments is recommended.