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<b><i>Introduction:</i></b> The objective of this study was to examine the association between type 2 diabetes mellitus (T2DM) and genes identified in previous genome-wide association studies (GWASs) in rural Han Chinese adults. <b><i>Methods:</i></b> This prospective study included 1,832 adults aged ≥18 years in Deqing without diabetes at baseline. The subjects were followed up for 8.7 years on average. We selected 45 susceptible tag single-nucleotide polymorphisms (SNPs) for T2DM that have been identified in GWASs and genotyped. A Cox model was constructed to calculate the adjusted hazard ratios (aHRs) for the association between SNPs and incident T2DM. <b><i>Results:</i></b> The incidence rate of T2DM was 12.0 per 1,000 person-years. After adjustment for covariates and a Bonferroni correction, rs17584499 of protein tyrosine phosphatase, receptor-type D (PTPRD), rs11257655 and rs10906115 of cell division cycle 123 gene (CDC123), and rs12970134 of melanocortin-4 receptor (MC4R) were significantly associated with incident T2DM. The aHRs for incident T2DM were 1.75 (95% confidence interval [CI]: 1.28–2.40) and 1.61 (95% CI: 1.27–2.04) in association with an increasing number of T alleles in rs17584499 and rs11257655 under an additive genetic model, and the aHR was 1.72 (95% CI: 1.33–2.22) with an increasing number of A alleles in rs10906115. The aHRs under the dominant model were 1.82 (95% CI: 1.25–2.66) for TT + CT versus CC of rs17584499 and 2.04 (95% CI: 1.47–2.86) for AA + AG versus GG of rs10966115. The aHRs under the recessive model were 2.99 (95% CI: 1.30–6.89) for TT versus CT + CC of rs17584499, 1.92 (95% CI: 1.39–2.70) for TT versus CT + CC of rs11257655, and 2.54 (95% CI:1.22–5.29) for AA versus AG + GG of rs12970134. In addition, an increased incidence of T2DM was significantly associated with the TA haplotype of rs11257655 and rs10906115 (aHR = 1.81, 95% CI: 1.12–2.92), while a decreased incidence was associated with the CG haplotype (aHR = 0.49, 95% CI: 0.35–0.68) and the CT haplotype of rs1111875 and rs5015480 (aHR = 0.61, 95% CI: 0.37–0.98). <b><i>Conclusion:</i></b> Variants of the PTPRD, CDC123, and MC4R genes were associated with the T2DM incidence in a rural Han Chinese population.