BACKGROUND: The first dose of measles-rubella (MR) vaccine is routinely administered to infants aged 9 months as part of a standard two-dose schedule. However, during large measles outbreaks and in other settings of increased circulation or increased risk, WHO recommends administering a supplementary dose at age 6 months to protect young infants. We aimed to assess the immunogenicity and safety of a first dose of MR vaccine administered to infants aged 6 months and its effect on the immune response to the routine MR vaccine at age 9 months. METHODS: This open-label, randomised trial enrolled healthy infants aged 6 months in Matlab, Bangladesh, who had never received an MR vaccine dose and had no history of measles or rubella. Using a computer-generated block randomisation scheme, infants were randomly assigned (1:1) to receive either two doses of the MR vaccine, one at age 6 months and the second at age 9 months (two-dose group), or one dose at age 9 months (one-dose group). Baseline characteristics were recorded for all enrolled participants at age 6 months. Blood samples were drawn for antibody assays before each vaccination and at final follow up when infants were aged 11 months. The primary outcome was immunogenicity of a first MR vaccine in infants aged 6 months or 9 months and the immunogenicity of a second MR vaccine in infants aged 9 months who received their first MR vaccine at 6 months. Immunogenicity was measured as the proportion of infants who seroconverted in the 12 weeks after vaccination at age 6 months or the 8 weeks after vaccination at age 9 months. Seroconversion was defined as a 4-times increase in IgG concentrations relative to the pre-vaccination concentrations or achieving seroprotective antibody concentrations between study timepoints. The modified intention-to-treat analysis included all infants who received MR vaccines per group assignment and had antibody results at baseline, 9 months, and 11 months. All enrolled infants were included in the safety analysis of the immediate reactions (observed by study staff at the fixed-site clinic in the first 30 min after vaccination), adverse events within 48 h of vaccination among infants in the two-dose group receiving their first MR vaccine at age 6 months, and adverse events observed by study staff or parents at any time during the study. The trial is registered on ClinicalTrials.gov, NCT03071575, and is closed to enrolment. FINDINGS: Between March 9, 2017, and March 18, 2018, 620 infants were enrolled and randomly assigned to the two study groups (312 in the two-dose group and 308 in the one-dose group). Of the 301 infants vaccinated at 6 months, 282 seroconverted for measles (94%, 95% CI 90-96), and 283 seroconverted for rubella (94%, 91-96). By 11 months, after receiving a second dose at age 9 months, 297 (cumulative 99%, 95% CI 97-100) infants seroconverted for measles and 297 infants seroconverted for rubella (cumulative 99%, 96-100). Of the 292 infants vaccinated at 9 months only, 291 seroconverted for both antigens by age 11 months (100%, 95% CI 98-100). 123 adverse events were observed; 72 in the two-dose group and 51 in the one-dose group, with no differences in severity (p=0·78) or outcomes (p=0·71) by study group. 12 (17%) events in the two-dose group and seven (14%) in the one-dose group were severe; most events were mild, resolved without sequelae, and were unrelated to the MR vaccine. One death occurred in the one-dose group before the infant received the 9-month dose of the vaccine, and therefore was deemed to be unrelated to the MR vaccine. INTERPRETATION: The data presented support use of MR vaccine at 6 months to protect young infants during measles outbreaks and in settings with increased risk or high transmission. We recommend additional studies to evaluate longer-term immunity based on age at vaccination. FUNDING: US Centers for Disease Control and Prevention. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.