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Background: Psychological distress may worsen during cancer treatment and affect well-being. Information on the prevalence of distress and its associated variables in cancer patients undergoing chemotherapy in rural Bangladesh has not been thoroughly explored. To address this, we aimed to assess psychological distress and its associated factors in patients with cancer undergoing chemotherapy. Methods: This cross-sectional study was conducted at a tertiary care hospital in rural Bangladesh. Only adult patients with cancer who were receiving chemotherapy were enrolled in this study. The validated Depression Anxiety Stress Scale was used to assess psychological distress. Frequency and percentages were used in descriptive analysis, and logistic regression analysis was performed to investigate potential associated factors for depression, anxiety, and stress. Results: Participants comprised 415 patients with a mean age of 46.3 years. The prevalence of depression, anxiety, and stress was 61.5%, 55.4%, and 22.0%, respectively. In the multivariate logistic regression analysis, patients with more than five family members and smokeless tobacco users had a significant association with depression, anxiety, and stress. In contrast, participants aged >60 years had a protective association with depression. Conclusions: Our findings show that patients with cancer receiving chemotherapy experience a high prevalence of depression and anxiety and that the use of smokeless tobacco and having six or more family members are associated with psychological distress. These findings will aid health professionals and policymakers in establishing and implementing improved care programs to ensure the greater mental health of cancer survivors, particularly in resource-limited settings. [ABSTRACT FROM AUTHOR]