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Background The reasons underlying the variation in response to neoadjuvant chemotherapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) remain poorly understood. The gut microbiome has been shown to influence response to chemotherapy in other tumour types.Objective Compare the gut microbiome composition between PDAC patients who responded well to NAT (R) and those who did not respond (NR).Design A prospective cohort study of NAT PDAC patients. Response was determined using biochemical and radiological criteria. Shotgun metagenomic sequencing of DNA extracted from stool samples was used to compare gut microbiome composition and the abundance of gene families associated with metabolism of chemotherapy agents between R and NR groups.Results Among 20 consecutive pancreatic cancer (PC) patients, 14 patients received at least 3 cycles of NAT so were included in the analysis and of these 7 had a favourable response (50%). There were 34 species that were significantly different in abundance between R and NR at baseline. This included Akkermansia muciniphilia, significantly increased in the gut microbiome of R patients (log fold change (logFC) +3.53, p<0.001) and Bacteroides vulgatus, significantly reduced in the baseline gut microbiome of R patients (logFC −1.98, p=0.001). At baseline, there was a significant reduction in the abundance of bacterial gene families associated with proteins involved in 5-fluorouracil (5-FU) metabolism, such as uridine monophosphate kinase (logFC −16.12; p=0.01), among R patients.Conclusions The baseline gut microbiome composition and gene family abundance of patients with PC associates with response to NAT. Differences include species known to influence chemotherapy responses in other malignancy types and gene families involved in the metabolism of 5-FU and irinotecan.