Introduction Clinical practice guidelines differ in their recommendations on first-line antihypertensive drug classes. No adequately powered randomised controlled trial have assessed all major drug classes against each other, and previous meta-analyses have mainly relied on pairwise meta-analyses for treatment comparisons.

Methods and analysis A systematic review and network meta-analysis will be carried out to assess the efficacy and acceptability of all major antihypertensive drug classes. PubMed and CENTRAL were searched on 21 February 2020 to identify randomised controlled trials with at least 1000 person-years of follow-up, assessing any antihypertensive agent against other agents or placebo. All trials fulfilling the inclusion criteria will be assessed for risk of bias using the second version of Cochrane’s risk of bias assessment tool. The study selection process, risk of bias assessment and data extraction are done by two authors in duplicate. Relative risks from individual trials will be combined in pairwise meta-analyses; in the absence of important intransitivity, random-effects network meta-analysis will be performed. The primary outcome for efficacy will be major adverse cardiovascular events, whereas the primary acceptability outcome will be treatment discontinuation for any reason. Additional outcomes include all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, heart failure and acute renal failure. The impact of differences within drug classes will be explored through alternative networks, including analysing thiazide-like and thiazide-type diuretics separately.

Ethics and dissemination This review will only process aggregated study level data and does not require ethical approval. The findings will be published in a peer-reviewed medical journal.

PROSPERO registration number CRD42020205482.