Background: Currently, there are no direct randomized control trials (RCTs) comparing gemcitabine and nab-paclitaxel (Gem-Nab) and FOLFIRINOX for advanced pancreatic cancer (APC). Thus, previous model-based cost-effectiveness analyses were based on indirect comparisons of RCT data. While it is well known that RCT-based efficacy does not often translate to real-world effectiveness, there is limited literature investigating the comparative cost-effectiveness of Gem-Nab versus FOLFIRINOX for APC in the real-world. The objective of this study is to examine the real-world cost-effectiveness of Gem-Nab versus FOLFIRINOX in patients with APC in Ontario, Canada. Methods: This population-based retrospective cohort study compared all patients treated with first-line Gem-Nab or FOLFIRINOX for APC with ECOG performance status 0-1 in Ontario from April 2015 to March 2019. Patients were linked to administrative databases to identify key characteristics and costing data. Using propensity scores and a stabilizing weights method, an inverse probability of treatment weighted cohort was developed. Mean survival and total costs were calculated over a 5-year time horizon, adjusted for censoring and discounted at 1.5% (per Canadian guidelines). Incremental cost-effectiveness ratio and net monetary benefit were computed (measured in life-years and quality-adjusted life years) to estimate cost-effectiveness from the public healthcare payer’s perspective. A sensitivity analysis was conducted using the propensity score matching method. Results: 1,988 patients were identified (Gem-Nab: 928, FOLFIRINOX: 1,060). Mean survival was lower for patients in the Gem-Nab group than the FOLFIRINOX group (0.98 versus 1.26 life-years, incremental -0.28 (95% confidence interval -0.47, -0.13)). Patients in the Gem-Nab group also incurred greater mean 5-year total costs (Gem-Nab: $103,884, FOLFIRINOX: $101,518). Key cost contributors include ambulatory cancer care, acute in-patient hospitalization, and systemic therapy drug acquisition. Gem-Nab was dominated by FOLFIRINOX, as it is less effective and more costly. Results from the sensitivity analysis were similar. Conclusions: In routinely treated unselected patients, Gem-Nab is likely more costly and less effective than FOLFIRINOX and therefore, not considered cost-effective at any commonly accepted willingness-to-pay threshold.