Background: Neoadjuvant therapy is increasingly recognized as an effective strategy prior to pancreatoduodenectomy. We investigate the role of neoadjuvant chemotherapy (NAC) followed by surgery and the predictive role of viable residual tumour cells histopathologically on outcomes. Methods: The study population comprised of 195 consecutive patients with pancreatic adenocarcinoma who were treated with either NAC or a surgery-first (SF) strategy. Histopathological viable tumour cells were examined in the NAC patients and clinicopathological factors were correlated with overall survival. Results: Forty-two patients (22%) were treated with NAC and 153 patients (78%) underwent SF. NAC was associated with higher estimated blood loss during surgery (928 mL versus 615 mL; P = 0.004), fewer (<15) excised lymph nodes (37% versus 17%; P = 0.015) and lower rates of lymphovascular invasion (65% versus 45%; P = 0.044) when compared with SF. Two-year survival of patients undergoing NAC was 63% and 51% in patients undergoing SF (P = 0.048). The 2-year survival of patients who had >65% residual tumour cells was 45% and 90% in patients who had <65% residual tumour cells (P = 0.022). Favourable responders (<65% viable tumour cells) were observed to have shorter operation time (<420 min) (55% versus 13%; P = 0.038), trend towards negative lymph node status (38% versus 10%; P = 0.067) and greater lymph node harvest in node positive patients (≥4 positive lymph nodes) (77% versus 37%; P = 0.045). Conclusion: The improved survival of patients undergoing NAC indicates effective management of micrometastatic disease and is an effective option requiring further investigation. Histopathological viable tumour cells after NAC was a surrogate marker for survival.