IntroductionPostprandial hypoglycaemia after gastric bypass surgery (also known as postbariatric hypoglycaemia or PBH) is an increasingly encountered clinical problem. PBH is characterised by meal-induced rapid spikes and consequent falls in glycaemia, resulting in both hypoglycaemia burden and high glycaemic variability. Despite its frequency, there is currently no approved pharmacotherapy. The purpose of this investigation is to evaluate efficacy and safety of empagliflozin 25 mg, a sodium-glucose cotransporter 2-inhibitor, to reduce glucose excursions and hypoglycaemia burden in patients with PBH after gastric bypass surgery.Methods and analysisIn a prospective, single-centre, randomised, double-blind, placebo-controlled, crossover trial, we plan to enrol 22 adults (≥18 years) with PBH after Roux-en-Y gastric bypass surgery (plasma or sensor glucose <3.0 mmol/L). Eligible patients will be randomised to receive empagliflozin 25 mg and placebo once daily, each for 20 days, in random order. Study periods will be separated by a 2–6 weeks wash-out period. The primary efficacy outcome will be the amplitude of plasma glucose excursion (peak to nadir) during a mixed meal tolerance test. Results will be presented as paired-differences±SD plus 95% CIs with p values and hypothesis testing for primary and secondary outcomes according to intention-to-treat. Secondary outcomes include continuous glucose monitoring-based outcomes, further metabolic measures and safety.Ethics and disseminationThe DEEP-EMPA trial (original protocol title: Randomized, double-blind, placebo-controlled crossover trialassessing the impact of the SGLT2 inhibitor empagliflozin onpostprandial hypoglycaemia after gastric bypass) was approved by the Bern Ethics Committee (ID 2021-01187) and Swissmedic (Ref. Number: 102663190) in October and November 2021, respectively. First results are expected in the first quarter of 2023 and will be disseminated via peer-reviewed publications and presented at national and international conferences. The acronym DEEP was derived from an overarching project title (DEciphering the Enigma of Postprandial Hyperinsulinaemic Hypoglycaemia after Bariatric Surgery), the term EMPA stands for the drug empagliflozin.Trial registration numberNCT05057819.