AIMS: To study the histological changes in non-neoplastic pancreas and the effects on pancreatic intraepithelial neoplasia (PanIN) after neoadjuvant chemoradiation therapy (NCRT) for pancreatic ductal adenocarcinoma (PDAC). METHODS AND RESULTS: We reviewed the archival H&E slides from 218 patients with PDAC who completed NCRT and pancreaticoduodenectomy. Sixty-five patients who underwent pancreaticoduodenectomy for PDAC without NCRT were used as controls. Various histological features were reviewed and correlated with NCRT and survival. The NCRT group had lower densities of PanIN2 (P = 0.004) and PanIN3 (P = 0.02) than the control group. The extent of fibrosis, the frequency of neuroma-like nerve proliferation and the frequency of islet cell aggregation were significantly higher in the NCRT group than in the control group (P < 0.05). The intensity of inflammation was less in the NCRT group than in the control group (P = 0.02). In the NCRT group, patents with moderate to severe fibrosis or grade 2 inflammation had poorer survival than those with mild fibrosis (P = 0.04) or those with grade 0 or grade 1 inflammation (P = 0.003), respectively. CONCLUSIONS: Non-neoplastic pancreatic tissue from patients who received NCRT had a reduced density of high-grade PanIN lesions, more pancreatic fibrosis, and higher frequencies of neuroma-like nerve proliferation and islet cell aggregation, but less inflammation, compared to tissue from those who did not receive NCRT.