Background: There are no established methods for pancreatic cancer (PAC) screening, but the NCI and the Pancreatic Cancer Action Network (PanCAN) are investigating risk-based screening strategies in patients with new-onset diabetes (NOD), a group with elevated PAC risk. Preliminary estimates of the cost-effectiveness of these strategies can provide insights about potential value and inform supplemental data collection. Using data from the Enriching New-Onset Diabetes for Pancreatic Cancer (END-PAC) risk model validation study, we assessed the potential value of CT screening for PAC in those determined to be at elevated risk, as is being done in a planned PanCAN Early Detection Initiative trial. Methods: We created an integrated decision tree and Markov state-transition model to assess the cost-effectiveness of PAC screening in patients aged ≥50 years with NOD using CT imaging versus no screening. PAC prevalence, sensitivity, and specificity were derived from the END-PAC validation study. PAC stage distribution in the no-screening strategy and PAC survival were derived from the SEER program. Background mortality for patients with diabetes, screening and cancer care expenditure, and health state utilities were derived from the literature. Life-years (LYs), quality-adjusted LYs (QALYs), and costs were tracked over a lifetime horizon and discounted at 3% per year. Results are presented in 2020 US dollars, and we took a limited US healthcare perspective. Results: In the base case, screening resulted in 0.0055 more LYs, 0.0045 more QALYs, and $293 in additional expenditures for a cost per QALY gained of $65,076. In probabilistic analyses, screening resulted in a cost per QALY gained of <$50,000 and <$100,000 in 34% and 99% of simulations, respectively. In the threshold analysis, >25% of screen-detected PAC cases needed to be resectable for the cost per QALY gained with screening to be <$100,000. Conclusions: We found that risk-based PAC screening in patients with NOD is likely to be cost-effective in the United States if even a modest fraction (>25%) of screen-detected patients with PAC are resectable. Future studies should reassess the value of this intervention once clinical trial data become available.