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It is unknown whether treatment costs for keratinocyte carcinoma (KC) and actinic keratosis (AK) can be lowered by spending more on chemoprevention.To examine the impact of 1-course treatment with topical fluorouracil (5-FU) on the face and ears on KC and AK treatment costs over 3 years.The Veterans Affairs Keratinocyte Carcinoma Chemoprevention trial compared the efficacy of topical 5-FU 5% with that of vehicle control cream for reducing KC risk. Trial data and administrative data on costs and utilization were analyzed to measure postrandomization encounters and treatment costs for KC and AK care. Adjusted models were used to test for statistically significant differences between treatment arms for number of treatment encounters and costs.One year after randomization, the control arm had a higher mean number of treatment encounters for squamous cell carcinoma (0.04) than the intervention arm (0.01) (P < .01). At 1 year, the intervention arm had lower treatment and dermatologic costs: $2106 (standard deviation, $2079) compared with $2444 (standard deviation, $2716) for the control patients (P = .02). After 3 years, the intervention arm incurred a cost of $771 less per patient.Care not provided or paid for by the Department of Veterans Affairs was not included. Results may not be generalizable to other payers.We found significant cost savings for patients treated with 5-FU.