Changes in health-related quality of life (HRQOL) among elderly patients with cancer before and after receiving curative treatment, such as chemotherapy, have always been an important consideration in physician-patient treatment decision-making. Although frailty assessment can help predict the effects of chemotherapy, there is a lack of relevant literature on its effectiveness in predicting post-chemotherapy HRQOL. Therefore, this study investigated the early predictive value of pre-chemotherapy frailty assessment for post-chemotherapy HRQOL among elderly patients with cancer receiving curative chemotherapy. From September 2016 to November 2018, this study enrolled elderly patients with cancer aged ≥ 65 years (N = 178), who were expected to receive chemotherapy at three hospitals in Taiwan. The mean age of patients was 71.70 years (SD = 5.46 years) and half of them were female (n = 96, 53.9%). A comprehensive geriatric assessment was performed to measure frailty in 178 participants one week before receiving chemotherapy (T0). Further, the HRQOL of the elderly patients with cancer was assessed again, four weeks after chemotherapy (T1). After controlling for demographic variables, this study evaluated the predictive value of frailty for HRQOL using a hierarchical regression analysis. A total of 103 (57.9%) participants met the frailty criteria. The results showed that 31.1%-56.7% of the variance in the seven domains of HRQOL could be explained by demographic variables and the presence or absence of frailty. This suggests that the presence or absence of frailty is an important predictor of the illness burden domain (β = 9.5; p < .05) of HRQOL. Frailty affects the illness burden domain of HRQOL in elderly patients with cancer. Finally, the administration of frailty assessments before treatment is recommended as a reference for patient treatment decision-making.