Purpose: The purpose of this study was to test the mediating effect of psychological distress in the relationship between chemotherapyrelated cognitive impairment (CRCI) and quality of life (QOL) in people with cancer. Methods: A purposive sample of 130 patients undergoingchemotherapy was recruited for the cross-sectional survey design. Data were collected from November 2014 to June 2015. Theinstruments were K-MMSE (Korean Mini-Mental State Examination), Everyday Cognition (ECog), Hospital Anxiety Depression Scale(HADS), and Functional Assessment of Cancer Therapy-General (FACT-G). Data were analyzed using descriptive statistics, correlation,and multiple regression using Baron and Kenny steps for mediation. Results: The mean score for objective cognitive function was 27.95and 69.32 for perceived cognitive decline. Overall quality of life was 91.74. The mean score was 17.52 for psychological distress. Theprevalence was 56.2% for anxiety and 63.1% for depression, and 20.0% for CRCI. There were significant correlations among the variables,objective cognitive function and self-reported cognitive decline, psychological distress, and quality of life. Psychological distresswas directly affected by CRCI. (R2=29%). QOL was directly affected by CRCI. Psychological distress and CRCI effected QOL (R2=43%). Psychological distress had a partial mediating effect (β= -.56, p qqqlt;.001) in the relationship between self-reported cognitive decline andquality of life (Sobel test: Z= -5.08, p qqqlt;.001). Conclusion: Based on the findings of this study, nursing intervention programs focusing onmanaging cognitive decline, and decreasing psychological distress are highly recommended to improve quality of life in cancer patients.