Objective To explore the relationship among nurses′ perception of high-performance work system, general self-efficacy and job well-being. Methods Totally, 327 nurses were surveyed with the Perceived High-Performance Work System Scale, the General Self-efficacy Scale and the Job Well-being Scale. Results Nurses scored (64.21±9.54) points in perceived high-perfor-mance work system, (30.61±6.57) points in general self-efficacy. Positive affect and job satisfaction dimensions of the Job Well-being Scale were positively correlated with perceived high-performance work system （P<0.05 for both）. Positive affect and job satisfaction dimensions of the Job Well-being Scale were positively correlated with general self-efficacy （P<0.05 for all）. Perceived high-performance work system was positively correlated with general self-efficacy (P<0.05). General self-efficacy was the mediating variable of nurses′ perceived high-performance work system and positive affect, and the mediating effect accounted for 17.25% of the total effect. General self-efficacy was the mediating variable between nurses′ perceived high-performance work system and job satisfaction, and the mediating effect accounted for 27.65% of the total effect. Conclusion Nurses′ perception of high-performance work system and general self-efficacy affect their job well-being. The establishment of a scientific and reasonable high performance work system in the hospital can improve nurses′ job well-being, and the improvement of self-efficacy will also enhance nurses′ job well-being.