Objective: PCSK2, is a proinsulin-processing enzyme playing a key role in regulating insulin and glucagon biosynthesis. The aims of this study is investigating the association between genetic variants of PCSK2 and various parameters of glucose homeostasis and progression from euglycemia to diabetes after a follow-up for 5 years. Methods: Total 1142 Chinese participants were recruited in the SAPPHIRe family study, and 759 participants received 5-yr follow-up. The anthropometric characteristics, plasma glucose & insulin concentration during OGTT, HOMA-IR and HOMA-beta at baseline and after 5-yr follow-up were measured. Twenty-nine common tagged SNPs of the PCSK2 gene were genotyped. The association between measured traits and SNP genotypes or haplotypes were analyzed with family based association test. Proportional hazard model was applied to analyze whether the specific haplotype was associated with the progression from euglycemia to diabetes during 5-yr follow-up. All the p values were adjusted for age, sex and BMI. Results: Haplotype of rs4814605 & rs1078199 was associated with HOMA-IR. Haplotype of rs6105750 & rs2206447 was associated with 1hr insulin concentration and AUCi during OGTT. Haplotype of rs890609 & rs2269023 was associated with fasting plasma glucose & insulin concentration, and HOMA-IR. Haplotype of rs2284912 & rs956347 was associated with fasting plasma glucose concentration, 1hr & 2hr glucose concentration and AUCg during OGTT. Haplotype of rs726256 & rs2328149 & rs3790336 & rs6044845 was associated with fasting plasma glucose concentration ad AUCg during OGTT. The participants with either GC haplotype of rs4814605 & rs1078199, or TA haplotype of rs4814608 & rs6136079 had significantly higher incidence of progressing to diabetes. Conversely, the participants with CT haplotype of rs2284912 & rs956347 had lower incidence of progression to diabetes. Conclusion: Significant associations between SNP haplotypes of PCSK2 and various traits of glucose homeostasis were found. Furthermore, individuals with specific haplotypes was associated with the progression to diabetes.