Background: Improved overall survival (OS) was observed in PREOPANC I after neoadjuvant hypofractionated radiation (HypoFx RT) (36 Gy/15 fractions) and chemotherapy compared with upfront surgery and adjuvant chemotherapy in localized pancreatic cancer (Pca). Long-course fractionated chemoRT (ConvFracRT) to 50.4 Gy/28 fractions is an alternative regimen which may deliver a biologically higher dose. Potential efficacy differences between HypoFxRT and ConvFracRT are not well described. Methods: Efficacy outcomes are assessed retrospectively after an institutional change in 2017 from preoperative ConvFracRT (50.4 Gy/28 fractions) to HypoFxRT (30-36 Gy/10-15 fractions). Patients with resectable and borderline resectable (BLR) Pca treated with neoadjuvant chemoradiation between 5/2012 and 11/2022 were reviewed (n=79). Baseline demographics and pathologic outcomes were compared using a Chi-square or t-test. Pathologic response was graded by Evans criteria (group 1 = complete response/minimal residual). Progression free survival (PFS) and overall survival (OS) were compared using the logrank test. The cumulative incidence of local failure was assessed indefinitely by CT imaging accounting for the competing risk of death. Results: During the study period, 79 patients (ConvFracRT=31 [39.2%], HypoFxRT =48 [60.8%]) were treated with chemoRT preoperatively. All patients received induction FOLFIRINOX (40 [50.6%]) or gemcitabine/nab-paclitaxel (39 [49.4%]) and sensitizing gemcitabine/fluoropyrimidine. The RT volume included the primary tumor and elective target coverage of the SMA/Celiac artery in all patients. There were no differences in baseline Ca 19-9 (median 206 vs 259 p=0.08), age (64 vs 71, p=0.1), male (46 vs 61 p=0.2), arterial abutment (44% vs 35% p=0.46) or proportion with BLR (69% vs 77% p=0.4) between the HypoFxRT or ConvFracRT groups. A greater proportion of HypoFxRT patients underwent resection (81% [39/48] vs 48% [15/31], p=0.002) compared to ConvFracRT secondary to higher rates of distant progression observed after ConvFracRT (42% [13/31] vs 16% [8/48] p=0.01). In all patients, improved median PFS (16 mo vs 8mo, p=0.04) and OS (37 mo vs 20 mo, p=0.04) were observed in the HypoFxRT group. In resected patients, rates of positive margin (13.3%% vs 10.3%, p =0.99) lymph node positivity (26.7% vs 43.6% p =0.29) and pathologic group 1 (40% vs 28%, p=0.51) were similar for ConvFracRT and HypoFxRT groups. The cumulative incidence of local failure at 2 years from surgery was similar in the HypoFxRT and ConvFracRT groups (22% vs 22% HR 0.975 95% CI [0.45-2.0]). Conclusions: Following a shift to HypoFxRT, no apparent compromise in pathologic tumor response, durability of local control, or survival was observed. This data supports the continued use of HypoFxRT within the neoadjuvant Pca treatment paradigm as more convenient alternatives to ConvFracRT.