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18 F positron emission tomography (PET) has a number of attributes that make it clinically attractive, including nearly 100% positron efficiency, very high specific radioactivity, and a short half-life of ≈ 110 minutes. However, the short half-life of 18 F and the poor nucleophilicity of fluoride introduce challenges for the incorporation of 18 F into complex molecules. Recently, the tetrazine- trans -cyclooctene ligation was introduced as a novel 18 F labeling method that proceeds with fast reaction rates without catalysis. Herein we report an efficient method for 18 F labeling of free cysteines of peptides and proteins based on sequential ligation with a bifunctional tetrazinyl-maleimide and an 18 F-labeled trans -cyclooctene. The newly developed method was tested for site-specific labeling of both c(RGDyC) peptide and vascular endothelial growth factor (VEGF)-SH protein. Starting with 4 mCi of 18 F- trans -cyclooctene and only 10 μg of tetrazine-RGD (80–100 μM) or 15 μg of tetrazine-VEGF (6.0 μM), 18 F-labeled RGD peptide and VEGF protein could be obtained within 5 minutes in 95% yield and 75% yield, respectively. The obtained tracers were then evaluated in mice. In conclusion, a highly efficient method has been developed for site-specific 18 F labeling of cysteine-containing peptides and proteins. The special characteristics of the tetrazine– trans -cyclooctene ligation provide unprecedented opportunities to synthesize 18 F-labeled probes with high specific activity for PET applications.