BackgroundThe role of adjuvant therapy in resected periampullary adenocarcinomas is equivocal due to contrasting data and limited prospective trials. MethodsThe Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MISSPAP), included data from 8 major academic institutions across India. Of the 1679 pancreatic resections, 736 patients with T3/T4 and/or Node positive adenocarcinomas (considered as high risk for recurrence) satisfying inclusion and criteria were available for analysis. Three (adjuvant): one (observation) matching, using T3/T4 T staging, nodal positivity and ampullary subtype, without replacement was performed by using the nearest neighbour matching method. ResultsOf 736 patients eligible for inclusion, 621 patients were matched of which 458 patients received adjuvant therapy (AT) (predominantly gemcitabine-based) and 163 patients were observed (O). With a median follow-up of 42 months, the 3-year, estimated 5-year OS and median OS for patients receiving AT and on observation was 67.1% (95% CI: 62.4–72.2) and 62% (95% CI: 54.2–70.7), 57.5% (52–63.8) and 51.1% (95% CI: 42.5%–61.4%) and 68.7 (95% CI: 59.6–73.1) months and 61.1 months (95% CI: 50.8–71.5), respectively. There was a statistical difference in OS in favour of patients receiving AT as compared to those on observation [Hazard ratio: 0.73 (95% CI: 0.54–0.97); p = 0.03]. Besides AT, presence of nodal involvement (median OS: 65.4 months vs not reached; p = 0.04) predicted for inferior OS. A trend for improved OS with AT was seen in most subgroups, with a greater effect in patients with T3/T4 T stage, nodal positivity and ampullary subtypes. ConclusionsThe results of the match-pair analysis suggest that adjuvant therapy improves overall survival in periampullary adenocarcinomas at high risk of recurrence with a greater benefit in T3/T4, node-positive and ampullary subtypes.