This study aimed to investigate the mediating role of mentalization in the relationship between five personality factors and psychopathology in patients with malignant tumors under chronic stress. The study was conducted using a descriptive-correlational method and structural equation modeling (SEM). The statistical population was all patients with malignant tumors in Urmia who referred to medical centers between October 1403 and July 1404. The sample consisted of 200 people (54% female and 46% male) who were selected by convenience sampling. The research tools included the Five Personality Factors Questionnaire (NEO-FFI), the Mentalization Scale (RFQ), and the Psychopathology Test (DASS-21). The data were analyzed by correlation and structural equation modeling. The results showed that neuroticism had the highest positive correlation with psychopathology (r=0.57), while mentalization showed a strong negative correlation with psychopathology (r=-0.53). The proposed structural model had a good fit (CFI=0.91, RMSEA=0.06) and showed that mentalization has a strong mediating role. Participants with higher levels of mentalization showed more positive behaviors and attitudes and a more effective capacity to cope with the stress of illness. The findings emphasize that the five personality factors, and especially neuroticism, are strong predictors of psychopathology in patients with malignant tumors.