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Background: Diabetes is associated with an increased risk of cancer. This study aimed to evaluate associations between recently reported type 2 diabetes (T2D) susceptibility genetic variants and cancer risk in a prospective cohort of Chinese patients with T2D. Methods: Seven single nucleotide polymorphisms (SNP) in IGF2BP2, CDKAL1, SLC30A8, CDKN2A/B, HHEX and TCF7L2, all identified from genome-wide association studies of T2D, were genotyped in 5900 T2D patients [age mean±SD=57±13 years, % males=46] without any known cancer at baseline. Associations between new-onset of cancer and SNPs were tested by Cox proportional hazard models with adjustment of conventional risk factors. Results: During the mean follow-up period of 8.5±3.3 years, 429 patients (7.3%) developed cancer. Of the T2D-related SNPs, the G-alleles of HHEX rs7923837 (hazard ratio [HR] (95% C.I.)=1.34 (1.08–1.65); P =6.7×10−3 under dominant model) and TCF7L2 rs290481 (HR (95% C.I.)=1.16 (1.01–1.33); P =0.040 under additive model) were positively associated with cancer risk, while the G-allele of CDKAL1 rs7756992 was inversely associated (HR (95% C.I.)=0.80 (0.65–1.00); P =0.048 under recessive model). The risk alleles of these significant SNPs exhibited combined effect on increasing cancer risk (per-allele HR (95% C.I.)=1.25 (1.12–1.39); P =4.8×10−5). The adjusted cancer risk was 2.41 (95% C.I. 1.23–4.69) for patients with four risk alleles comparing to patients without risk allele. Conclusions: T2D-related variants HHEX rs7923837, TCF7L2 rs290481 and CDKAL1 rs7756992 increased cancer risk in patients with diabetes. Impact: Our findings provide novel insights into the pathogenesis of cancer in diabetes. [ABSTRACT FROM AUTHOR]