We prospectively evaluated the association of tumor response with change of quality of life (QOL) in patients with advanced gastrointestinal tumors receiving palliative chemotherapy. Out of 133 eligible patients, 90 (68%) completed the European Organization for Research and Treatment Quality of Life Questionnaire C-30 (EORTC QLQ C-30) at baseline and at regular intervals during palliative chemotherapy. Among the 90 available patients, 88 patients could be evaluated for response, and 32 (36%) responded. Taking into account 32 patients who had stable disease, 64 (73%) achieved a clinical benefit, defined as an objective response or stable disease. Improvement in the emotional functioning or global QOL was observed before the fourth cycle of chemotherapy in responders (P = 0.039) and patients with clinical benefit (P = 0.026). Grade 3 or 4 toxic effects occurred in 39% of patients; however, this did not adversely affect the global or other domains of QOL. Therefore, change of QOL during the chemotherapy was closely related with clinical outcomes. We should apply the QOL assessment to all patients who received palliative chemotherapy for their gastrointestinal tumors.