Abstract: To elucidate the mechanism of tolerant of exposed Perilla frutescens (L.) Britt. to cadmium stress, a set of hydroponic culture experiments were set up to analyze the differential expressions of proteins in P. frutescens leaves after 3 weeks of exposure. The study used two-dimensional electrophoresis technique and added Cd²⁺ to hydroponic solutions of the hydroponic culture experiments. Based on the results, 25 proteins changed in P. frutescens leaves and 20 of them were identified by LC-MS/MS analysis. The identified proteins included 3 proteins related to photosynthesis, 11 proteins related to energy metabolism, 1 protein related to stress, 2 proteins related to protein metabolism, 1 protein related to gene expression, 1 structural protein, and 1 protein related to biosynthesis and detoxication. Under Cd²⁺ concentrations of 2.0 mg·kg^-1, 5.0 mg·kg^-1 and 10.0 mg·kg^-1, ATP synthase, serine carboxypeptidases and plant cytochrome P450 up-regulated in P. frutescens leaves, but oxygenase large subunit, ribosomal protein S3 and actin down-regulated in P. frutescens leaves. Furthermore, photosystem Ⅱ stability/assembly factor HCF136 and acyl-CoA thioesterase up-regulated in low Cd²⁺ concentration of 2 mg·kg^-1, but down-regulated in higher Cd²⁺ concentrations of 5 mg·kg^-1 and 10 mg·kg^-1. Phosphoribulokinase/uridine kinase family protein up-regulated under 2 mg·kg^-1 and 5 mg·kg^-1 Cd²⁺ concentrations, but no difference was detected under 10 mg·kg^-1 Cd²⁺ concentration. Additionally, retrotransposon protein involved in gene expression down-regulated under 10 mg·kg^-1 Cd²⁺ concentration. The results indicated that P. frutescens strengthened energy metabolism, reduced photosynthesis, altered protein metabolism and gene expression, and improved detoxification under Cd²⁺ stress, and thereby enhanced P. frutescens cadmium tolerance.