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Recent studies have shown that patients with diabetes mellitus have a higher risk of tumorigenesis. However, the effect of glycemic variability on tumorigenesis among diabetic patients has not been well investigated. Hence, we performed a retrospective cohort study to analyze the effect of visit-to-visit hemoglobin A1c (HbA1c) variability and later onset of malignancies.This study included 2640 patients with diabetes mellitus 50 years or older. To analyze visit-to-visit glycemic activity, we calculated intrapersonal SD of all recorded HbA1c and used SD-HbA1c as a measure of glycemic variability. Because the number of individual visits varied, we divided SD-HbA1c by visit times in order to adjust for the potential influence of visit time difference between individuals. Patients were divided into quartiles according to their HbA1c variability, and Cox regression models were used to evaluate the association between glycemic variability and later onset of tumorigenesis.Three hundred thirty patients (12.5%) developed malignancy during follow-up. The median follow-up period was 1511 days (4.1 years; interquartile range, 2487.5 days). Relative to the group with the lowest glycemic variability (first quartile), the groups with higher glycemic variability showed a dose-dependent association with tumorigenesis. The odds ratios for the second, third, and fourth quartiles were 1.20 (95% confidence interval, 0.88–1.65), 1.43 (1.02–2.00), and 2.19 (1.52–3.17), respectively. The mean HbA1c and diabetes mellitus duration periods were not significantly associated with tumorigenesis. This result was consistent when limiting the number of covariates.These results demonstrated that visit-to-visit HbA1c variability is a potential risk factor for later tumorigenesis. The association may be mediated by oxidative stress or hormone variability. Routine cancer screening may be suggested for diabetic patients with unstable glycemic control.