Patients on maintenance haemodialysis (MHD) face social isolation due to the far-reaching effects of their disease and treatment. Based on the Transactional Model of Stress and Coping, we analysed the relationship between perceived stress and social isolation in patients, and the mediating role of internal health-related locus of control (IHLC) from the perspective of co-existence of perceived helplessness (HEL) and perceived self-efficacy (SEL). We used structured questionnaires to investigate 332 cases of young and middle-aged MHD patients in four tertiary hospitals in Guangdong, China. Polynomial regression and response surface analysis were conducted, along with tests of mediating effects on the data. The research was based on STROBE guidelines. The results showed that perceived stress is significantly and positively associated with social isolation. When the HEL and SEL of perceived stress were congruent, the joint effect of the two was in a positive curvilinear relationship to social isolation, when the two were incongruent, the risk of social isolation was lower for "low HEL-high SEL" patients compared to the "high HEL-low SEL" combination. The more congruent in HEL -SEL, the lower the risk of social isolation for the patients, with the IHLC playing a mediating role in this association. This study reveals that the coexistence of perceived stress's HEL and SEL affects social isolation through congruent and incongruent matching mechanism, providing additional explanations for the mechanism of occurrence of patients' social isolation.© 2023 John Wiley & Sons Ltd.