Background: The efficacy of FFX and GNP as 1LTx of mPC were established in phase 3 trials against Gemcitabine alone. However, no head‐to‐head trial has been performed. This analysis was conducted to compare the use of the two regimens in the 1LTx of mPC patients (pts). Methods: Retrospective study collected data of pts diagnosed with mPC (ECOG 0‐1) that received FFX or GNP as 1LTx at the Jewish General Hospital between 2010‐2016. Pt selection for 1LTx was based in ASCO Guidelines 2016 Criteria (AGC2016). Progression free survival (PFS) and overall survival (OS) were estimated using a Kaplan Meier method. Rate of 1LTx discontinuation and start of 2LTx was compared using two‐sided Fisher's exact test. Results: Among 75 pts with mPC (median age 69), 44 (59%) received FFX and 31 (41%) received GNP. In the FFX group 57% were male and 24 pts (55%) had primary tumors localized in the pancreatic head (PTPH). The majority of patients [n = 36 (82%)] had ECOG 1 at the start of FFX. The most common grade 3‐4 adverse events (AEs) were gastrointestinal symptoms (GI) [n = 12 (27%)], neutropenia (N) [n = 9 (20%)], fatigue (F) [n = 5 (11%)], and peripheral sensory neuropathy (PSN) [n = 2 (4%)]. In the GNP group 61% were male and 20 pts (65%) had PTPH. The majority of pts [n = 23 (74%)] had ECOG 1 at the start of GNP. The most common grade 3‐4 AEs were F [n = 8 (26%)], N [n = 4 (13%)], GI [n = 3 (10%)], and PSN [n = 2 (7%)]. Similar rates of 1LTx discontinuation due to AEs were seen in both groups: 5 pts (11%) in the FFX group due to GI, 2 pts (6.5%) in the GNP group due to F (p = 0.69). In the FFX cohort, 68.2% (30/44) went on to 2LTx whereas in the GNP cohort, 32% (10/31) received 2LTx (p = 0.0001). Of the FFX cohort receiving 2LTx, 40% (12/30) received GNP. The median PFS for the FFX and GNP groups were 5.75 and 4.63 months, respectively, and were not statistically significant (p = 0.523). The OS with FFX and GNP was 9.23 vs. 6.6 months (p = 0.09). Conclusions: For pts selected as per ASC2016, FFX and GNP cohorts showed similar PFS, OS, AEs, and 1LTx discontinuation rate. Our data highlight the importance of optimal therapeutic sequencing to prolong OS. A randomized trial will be needed to confirm 1LTx in mPC.