OBJECTIVE: The purpose of this study was to clarify the relationship between hope, psychological distress, and quality of life (QOL) of patients with advanced cancer undergoing cancer pharmacotherapy and their related factors. METHODS: Participants were patients with advanced lung, colorectal, and breast cancer undergoing outpatient pharmacotherapy. The Herth Hope Index, Hospital Anxiety and Depression Scale, and Functional Assessment of Cancer Therapy-General were used as measurement tools in a cross-sectional survey. Data were analyzed using descriptive statistics, correlation analysis, t-test, one-way analysis of variance (ANOVA), and Structural Equation Modeling (SEM). RESULTS: The number of valid responses to the questionnaire survey was 200 (91.7%). SEM included hope, psychological distress, QOL, social support, economic deprivation, physical symptoms, and performance status. The goodness of fit index for SEM was 0.989, adjusted goodness of fit index was 0.960, comparative fit index was 1.000, and root mean square error of approximation was 0.001. Hope had a negative impact on psychological distress (β = - 0.46) and a positive impact on QOL (β = .19). CONCLUSION: Hope was shown to be a predictor of psychological distress and QOL in patients with advanced cancer receiving pharmacotherapy. Predictors of hope were social support and economic deprivation. The results suggest that early intervention for patients with characteristics that tend to lower levels of hope is effective in reducing patient anxiety and depression and improving QOL.