Aims and ObjectivesTo determine whether self-efficacy mediates the relationship between Symptom Clusters (SC) and quality of life (QOL) in patients with myasthenia gravis (MG). BackgroundThe QOL in patients with MG can be affected not only by the SC but the self-efficacy in previous studies, while the latter may also be contributed by the former. However, it is still unclear whether self-efficacy mediates the relationship between SC and QOL in patients with MG. DesignA cross-sectional survey was conducted in patients with MG who were recruited from our institution from October 2021 to March 2022, which was reported in line with the STROBE guidelines. MethodsThe hypothetical model was tested and all the effects of SC and self-efficacy on QOL were estimated based on structural equation modelling (SEM) analysis after conducting a confirmatory factor analysis of the scales in a separate cohort. ResultsThree scales for symptoms (four summated items), self-efficacy (four plus one parcelled item) and MG-QOL (three summated items) were validated according to the confirmatory factor analysis in 72 patients. An SEM analysis of another 310 participants revealed that SC exerted significant direct effects on QOL and self-efficacy, with values of .585 and -.293, respectively, and self-efficacy also had a significant effect on QOL (-.141). The indirect effect of SC on QOL via self-efficacy was .041, accounting for 6.6% of the overall effect. Male and female patients did not differ in the direct and indirect effects of symptoms on QOL. ConclusionsThis study suggests that, although self-efficacy partially mediates the relationship between SC and QOL in patients with MG, worsening of symptoms remains the leading contributor to the decreased QOL. Relevance to Clinical PracticeThese results may provide a potential clue for doctors, nurses, and other caregivers to optimise treatment strategies for targeted patients with MG. Patient or Public ContributionInvolved in developing and answering research questions, management and conduct.