Background: Besides age, many risk factors have been associated with elevated cancer risk. Understanding cancer incidence rates among patients with single or multiple risk factors can help inform cancer prevention and detection efforts. Methods: A retrospective observational analysis was conducted on individuals aged 50-79 in 2020 using Optum’s de-identified Clinformatics Data Mart Database which includes Medicare Advantage (MA) (vast majority aged 65+) and commercially insured members (mostly below 65 and employed). Patients with no prior cancer diagnosis (continuously enrolled with no cancer claims for one year) and with cancer risk factors were identified using ICD-10-CM and CPT-4 codes, including autoimmune-related chronic inflammation (diabetes, inflammatory bowel disease, asthma, or rheumatoid arthritis) (INFLAM AUTO); non-autoimmune related chronic inflammation (fatty liver disease, obesity, or cirrhosis/chronic hepatitis B/C) (INFLAM NONAUTO); immunodeficiency (primary or secondary immunodeficiency, HIV, or status post organ transplant); and smoking. Cancer incidence rate ratios (IRR) were calculated by comparing one-year cancer incidence rate among the groups with risk factors versus the general population by insurance type (IRR>1 means elevated risk of cancer). Groups with evidence of any risk factor and combinations of risk factors were assessed. Statistical significance of IRRs was evaluated using logistic regression models adjusting for demographic characteristics. Results: Cancer incidence rates of 1.12% and 2.11% were observed among the approximately 1.3 and 2.4 million general population aged 50-79 in commercial and MA plans, respectively. Enrollees with any of the risk factors or combinations analyzed had statistically significantly elevated risk of cancer (IRRs>1.00, p<0.05). Commercially insured groups with highest risk included transplant (IRR=7.68, prevalence=0.02%), immunodeficient and smokers (IRR=3.66, prevalence=0.16%), cirrhosis/chronic hepatitis B/C (IRR=2.61, prevalence=0.41%), INFLAM AUTO and smokers (IRR=2.43, prevalence=3.56%), and smoker (IRR=2.33, prevalence=11.11%). Results in MA were generally consistent with the commercial plan (Table). Conclusions: Patients in both commercial and MA plans with any risk factor experienced significantly elevated cancer risk. Cancer prevention and screening strategies can be informed by risk levels among different patient subgroups to optimize resource allocation.