Introduction: Post Whipple's Pancreatico-duodenectomy (PD) the major concern is pancreaticojejunostomy (PJ) leak which leads to post operative pancreatic fistula (POPF), post pancreatectomy haemorrhage(PPH), delayed gastric emptying (DGE) ,sepsis. sometimes mortality.Hydrocortisone and indomethacin have been postulated to reduce post operative pancreatitis and thus PJ leak. Methods: Between Jan 2018 - April 2019, 146 patients for Whipple's PD were included. Only high risk patient (n= 105)with >40% of acini (marker of soft pancreas) on frozen section of transection margin were randomized to intravenous (iv) hydrocortisone, per rectal (PR) indomethacin or placebo (3 groups ,35 in each group). All patients received total 8 doses of iv treatment (8 hourly) and 6 doses of PR treatment (12 hourly). 100 ml NS and glycerin suppository were the placebo drugs. Primary end-points were overall major complications(Clavien Dindo 2-5). Results: Hydrocortisone group had less major complications compared to placebo(overall 14.3% vs 40.0%; P value = 0.003). POPF (8.6% vs 20%) and DGE (14.3% vs 22.9%) were also lower in hydrocortisone group Indomethacin group did not reduce major complications compared to placebo (overall, 37.2% vs 40%; p value = 1.00). POPF (17.1% vs 20%) and PPH (11.4% vs 14.3%) Although, DGE is significantly less in indomethacin group (14.3% vs 22.9%; p value = 0.001). 30 day mortality was zero in all the groups. Conclusions: Hydrocortisone treatment significantly reduces major postoperative complications in high risk patients after Whipple's PD whereas Indomethacin treatment does not as compared to placebo.