Background <p>Sarcopenia is an important prognostic factor for cancer patients. Here, we prospectively examined the effects of sarcopenia on progression-free survival (PFS) and overall survival (OS) of patients with pancreatic ductal adenocarcinoma (PDAC) treated with first-line gemcitabine and nab-paclitaxel (GnP).</p> Methods <p>This single-center prospective study enrolled patients with unresectable PDAC treated with first-line GnP between May 2020 and January 2024. The skeletal muscle index (SMI) was used as an index of sarcopenia. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019 diagnostic algorithm. PFS and OS of patients with/without sarcopenia were compared. The univariate and multivariate analyses were performed to identify variables significantly associated with prognosis. Changes in skeletal muscle mass (SMM) were also compared with patient prognosis.</p> Results <p>Of the 66 patients who received first-line GnP, 21 had sarcopenia. The median PFS of those with or without sarcopenia was 3.7 and 6.9&#xa0;months, respectively (<i>p</i> = 0.045); the median OS was 8.4 and 15.1&#xa0;months, respectively (<i>p</i> = 0.006). Multivariate analysis identified sarcopenia as an independent prognostic factor for PFS and OS (<i>p</i> = 0.009, <i>p</i> = 0.005, respectively). The rates of major grade 3 or 4 adverse events were significantly higher in the sarcopenia group (<i>p</i> = 0.008). In the sarcopenia group, an early increase in SMM was an independent good prognostic factor (<i>p</i> = 0.041).</p> Conclusions <p>Sarcopenia is an independent indicator of poor prognosis in patients with PDAC treated with first-line GnP. Increasing SMM in patients with sarcopenia may prolong PFS.</p>