Objective To explore the impact of sense of coherence（SOC） and illness intrusiveness on the demoralization syndrome among young and middle-aged patients undergoing maintenance hemodialysis（MHD），and to test the mediating effect of SOC between illness intrusiveness and demoralization syndrome in this disease population. Methods Using convenience sampling，a total of 215 young and middle-aged MHD patients from a tertiary hospital in Shaoxing were investigated by the general information questionnaire，Chinses version of Demoralization Scale-Ⅱ，Illness Intrusiveness Rating Scale，and Sense of Coherence-13 from March 2022 to March 2023. Results A total of 203 valid questionnaires were collected，with a recovery rate of 94.4%. The scores of demoralization syndrome，illness intrusiveness，and SOC among the 203 young and middle-aged MHD patients were （13.64±4.68），（44.05±13.05），and（49.80±14.75），respectively. SOC had a negative impact on demoralization syndrome in young and middle-aged MHD patients（P<0.001），while illness intrusiveness had a positive impact on demoraliza-tion syndrome（P<0.001）. SOC partially mediated the relationship between illness intrusiveness and demoralization syndrome in young and middle-aged MHD patients（β=0.52，P<0.001），accounting for 60.5% of the total effect. Conclusion SOC and illness intrusiveness have impacts on the demoralization syndrome in young and middle-aged MHD patients. The level of illness intrusiveness can influence the level of demoralization syndrome by affecting the level of SOC. Nursing managers can adopt effective measures to reduce the degree of illness intrusiveness and enhance the SOC of young and middle-aged MHD patients，thereby reducing the adverse impact of demoralization syndrome on this patient group.