Objective To explore the relationship between spiritual well-being and positive psychological quality in patients with advanced lung cancer, and to identify how benefit finding mediate between spiritual well-being and self-esteem. Methods With cross-sectional survery design, 215 patients with advanced lung cancer treated in oncology and radiotherapy wards of two 3A hospitals in Anhui province were surveyed with a domographic questionnaire, the Revised Life Orientation Test (LOT-R), the Self-Esteem Scale (SES), the Benefit Finding Scale (BFS), and the Function Assessment of Chronic Illness Therapy-Spiritual Well-being Scale (FACIT-Sp-12). Survey data were used to build up a mediation model which was later tested with Bootstrap method. Results The patients scored (24.28±9.98 ) points in spiritual well-being, (31.35±3.80) points in self-esteem, and (43.35±11.01) points in benefit finding respectively, and the median score of optimism was 16. Spiritual well-being varied significantly by different age groups, education levels, family income levels, lengths of time intervals since diagnosis confirmation, numbers of completed chemotherapy cycles, and having religious belief or not (P<0.05,P<0.01). Correlation analysis showed that there was significantly positive correlation between each pair of the 4 variables (optimism, self-esteem, benefit finding and spiritual well-being) (P<0.01 for all). The mediation model showed optimism and self-esteem had direct effect on spiritual well-being at 0.33 and 0.22 respectively, each accounting for 60% and 63% of total effect. Benefit finding mediated between optimism or self-esteem and spiritual well-being, with the indirect effect of 0.22 and 0.13 respectively, each accounting 40% and 37% of total effect. Conclusion Optimism and self-esteem can not only directly influence spiritual well-being, but also exert indirectly effect on spiritual well-being through the mediating role of benefit finding.