Objectives: There have been a number of studies showing an association between diabetes and cancer risk and a growing concern that this risk maybe linked to insulin therapy. This study aimed to (1) to assess the effect of insulin exposure on the risk of developing solid cancer among patients with diabetes mellitus; and (2) to explore the role of HbA1c value in modifying the risk. Methods: The study used the General Practice Research Database (GPRD), a large UK-based research database of patient electronic health records from general practitioners, to explore the use of insulin on the risk of cancer. Cox's Proportional hazards models were used to estimate the hazard ratio of solid tumors, all sites and selected individual sites, by types of antidiabetic therapy. The potential modifying role of diabetes control as measured by hemoglobin A1c (HbA1c) was also explored. Results: The study cohort contained a total of 230,330 patients with claims for antidiabetic therapy. The study found that use of insulin alone or in combination with other oral agents was associated with an increased risk of cancer. Insulin use was strongly associated with pancreatic cancer risk (HR=1.875, 95% CI 1.261, 2.787 for insulin alone and HR=2.330, 95% CI 2.007, 2.705 for insulin with oral agents). Moreover, HbA1c appears to be a risk factor for pancreatic cancer (HR=1.385, 95% CI 1.324, 1.450). The risk of pancreatic cancer was similarly increased for premixed and intermediate-acting insulin when compared with short-acting insulins. Role of HbA1c value in modifying the risk of cancer among patients with diabetes varies across different cancer types. Conclusion: Use of insulin, alone or in combination with oral agents, may pose a strong risk for pancreatic cancer and overall cancer. Use of insulin alone was also associated with an increased risk of colorectal cancer. These data suggest that there may be more than one mechanism by which insulin therapy impacts the risk of cancer among diabetics. Glucose control appears to impact the risk of pancreatic cancer, though it may be an independent factor for some common tumors. Caution should be used when prescribing insulin to patients for diabetes management.