Background: Gemcitabine plus nab-paclitaxel and fluorouracil (5-FU)-based chemotherapy, such as FOLFIRINOX and FOLFOX, are standard treatment for unresectable PDAC. While older age and poor performance status (PS) are established negative prognostic factors, most clinical trials exclude these vulnerable populations. We aimed to assess the impact of older age and reduced PS in a real-world cohort of patients with PDAC who received chemotherapy. Methods: We retrospectively reviewed patients with unresectable or metastatic PDAC treated with first line (1L) therapy at Mount Sinai Health System from 1/2012 to 12/2021. We evaluated the association between age (≥ 75 vs. < 75) and PS (ECOG PS ≥ 2 vs. < 2) on overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier estimates and multivariable Cox proportional hazards regression models. Chemotherapy tolerability was compared between these vulnerable and non-vulnerable populations using Chi-squared and Mann-Whitney tests. Results: 254 patients were evaluable. The median age of the full cohort was 66 years, and 130 (51.2%) patients were male. All patients had locally advanced (29.8%) or metastatic disease (70.2%). 47.6% of patients received gemcitabine-based and 49.6% received 5-FU-based 1L therapy. 41 patients (16.1%) had ECOG PS ≥ 2, and 60 (23.6%) were 75 or older. The type of 1L chemotherapy and rate of adverse events (AEs) requiring dose change or discontinuation did not differ significantly between patients with ECOG PS ≥ 2 and PS < 2. However, patients with ECOG PS ≥ 2 received a shorter duration of therapy (median 2.6 vs. 3.4 months, P = 0.018), and the reason for discontinuation was more often due to clinical deterioration (56.1% vs. 29.6%, P = 0.004). As a result, fewer continued on to second-line (2L) therapy (29.3% vs. 51.2%, P = 0.016). ECOG PS ≥ 2 was associated with worse OS (HR 1.6, 95% CI 1.1-2.4, P = 0.016) in univariate analysis but not in multivariate analysis. ECOG PS ≥ 2 correlated with worse PFS in both univariate and multivariate analyses (HR 1.6, 95% CI 1.1-2.3, P = 0.009; HR 1.5, 95% CI 1.1-2.2, P = 0.023). Patients older than 75 were more likely to receive gemcitabine-based therapy (83.3% vs. 40.2%, P< 0.001). While no significant differences in duration of therapy, rate of AEs, or reasons for discontinuation were observed based on age, older patients were less likely to receive 2L therapy (28.3% vs. 53.6%, P = 0.001). Age ≥ 75 was associated with worse OS (HR 1.6, 95% CI 1.19-2.25, P = 0.003) and worse PFS (HR 1.4, 95% CI 1.05-1.89, P = 0.024) in univariate but not multivariate analyses. Objective response rates did not differ based on PS or age. Conclusions: Reduced PS was associated with worse clinical outcomes and poor chemotherapy tolerance, but older patients appeared to tolerate gemcitabine-based regimens. Future studies should more specifically address the treatment needs of frail and elderly patients.