Sarcopenia, defined as decrease in skeletal muscle mass (SMM) and strength, might be associated with reduced survival. We investigated the impact of sarcopenia and decrease in SMM in patients with advanced pancreatic cancer during FOLFIRINOX (FX) therapy. Consecutive sixty-nine patients who received FX were evaluated. Skeletal muscle index (SMI) (cm2/m2) was used to evaluate SMM. The cut-off value of sarcopenia was defined as SMI <42 for males and <38 for females, based on the Asian Working Group for sarcopenia criteria. Sarcopenia was diagnosed in thirty-three (48 %) subjects. Comparison of baseline characteristics of the two groups (sarcopenia group: non-sarcopenia group) showed a significant difference in sex, tumour size and BMI. There was no significant difference in the incidence of adverse events with grades 3–5 and progression-free survival (PFS) during FX between the two groups (PFS 8·1 and 8·8 months; P = 0·88). On the multivariate analysis, progressive disease at the first follow-up computed tomography (hazard ratio (HR) 3·87, 95 % CI 1·53, 9·67), decreased SMI ≥ 7·9 % in 2 months (HR 4·02, 95 % CI 1·87, 8·97) and carcinoembryonic antigen ≥ 4·6 (HR 2·52, 95 % CI 1·10, 6·11) were significant risk factors associated with poor overall survival (OS), but sarcopenia at diagnosis was not. OS in patients with decreased SMI of ≥7·9 % and <7·9 % were 10·9 and 21·0 months (P < 0·01), respectively. In conclusion, decrease in SMM within 2 months after the initiation of chemotherapy had significantly shorter OS, although sarcopenia at diagnosis did not affect OS. Therefore, it might be important to maintain SMM during chemotherapy for a better prognosis.