Background: Systematic review of previous randomised controlled trials concluded that the non-antibiotic option of methenamine hippurate may be effective for urinary tract infection (UTI) prevention but outlined the need for further large, well-conducted randomised trials. We aimed to satisfy this requirement by testing its efficacy, compared to the current standard prophylactic treatment of daily low-dose antibiotics. Methods: This randomised, non-inferiority trial recruited from eight UK centres. Women with recurrent UTI, requiring prophylactic treatment, were randomly assigned (1:1), (using permuted blocks of variable length via a web-based system), to receive antibiotic prophylaxis or methenamine hippurate for 12-months. Treatment allocation was not masked and crossover between arms was permitted. The primary outcome was the absolute difference in symptomatic, antibiotic-treated UTI incidence during treatment. The non-inferiority margin was one UTI episode per person-year. Analyses performed in a modified intention-to-treat (mITT) population comprised all participants observed for at least six months. Trial registration was via ISRCTN registry, ISRCTN70219762. Findings: Between June 23, 2016 and June 20, 2018, 240 participants were randomised to antibiotic prophylaxis (n=120) or methenamine hippurate (n=120). The mITT analysis comprised 205 (85%) participants [102 (85%) antibiotics, 103 (86%) methenamine hippurate]. The incidence of antibiotic-treated UTI during the 12-month treatment period was 0·89 episodes per person-year (95% CI 0·65-1·12) in the antibiotic group and 1·38 (1·05-1·72) in the methenamine hippurate group with an absolute difference of 0·49 (90% CI 0·15-0·84) confirming non-inferiority. Adverse reactions were reported by 34/142 (24%) and 35/127 (28%) participants receiving antibiotics and methenamine hippurate respectively and the majority were mild. Interpretation: Non-antibiotic prophylactic treatment using methenamine hippurate should now be considered as a first-line option in women with a history of recurrent UTI episodes, given the robust demonstration of non-inferiority to daily antibiotic prophylaxis seen in this trial. Clinical Trial Registration Details: ISRCTN registry, ISRCTN70219762. Funding Information: National Institute for Health Research Health Technology Assessment Programme. Declaration of Interests: CH, HM, TH,TC , WK, JL, AAb, LV, RF, KW and AAl report grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme pertaining to the reported study. All other authors have nothing to declare. Ethics Approval Statement: The study protocol was approved by North East Tyne and Wear South Research Ethics Committee (15/NE/0381) and has been published. All participants provided written informed consent.