Abstract Background Histo-blood group antigen (HBGA) status may affect vaccine efficacy due to rotavirus strains binding to HBGAs in a P genotype–dependent manner. This study aimed to determine if HBGA status affected vaccine take of the G3P6 neonatal vaccine RV3-BB. Methods DNA was extracted from stool samples collected in a subset (n = 164) of the RV3-BB phase IIb trial in Indonesian infants. FUT2 and FUT3 genes were amplified and sequenced, with any single-nucleotide polymorphisms analyzed to infer Lewis and secretor status. Measures of positive cumulative vaccine take were defined as serum immune response (immunoglobulin A or serum-neutralizing antibody) and/or stool excretion of RV3-BB virus. Participants were stratified by HBGA status and measures of vaccine take. Results In 147 of 164 participants, Lewis and secretor phenotype were determined. Positive vaccine take was recorded for 144 (97.9%) of 147 participants with the combined phenotype determined. Cumulative vaccine take was not significantly associated with secretor status (relative risk, 1.00 95% CI, .94–1.06; P = .97) or Lewis phenotype (relative risk, 1.03 95% CI, .94–1.14; P = .33), nor was a difference observed when analyzed by each component of vaccine take. Conclusions The RV3-BB vaccine produced positive cumulative vaccine take, irrespective of HBGA status in Indonesian infants. Population differences in histo-blood group antigen status may contribute to the varying performance of oral rotavirus vaccines. This study revealed that the RV3-BB vaccine produced positive cumulative vaccine take, irrespective of histo-blood group antigen status in Indonesian infants.