Abstract Background Rotavirus vaccine effects appear lower in countries with high child mortality rates and high diversity of rotavirus genotypes. Some evidence suggests diminished vaccine efficacy (VE) against the G2P[4] genotype, which is heterotypic with existing monovalent rotavirus vaccine formulations. Most studies assessing genotype-specific VE have been underpowered and inconclusive. Methods We pooled individual-level data from ten Phase II and III clinical trials of monovalent rotavirus vaccine containing G1 and P[8] antigens (RV1). We estimated VE against any-severity and severe (Vesikari score ≥11) rotavirus gastroenteritis (RVGE) using binomial and multinomial logistic regression models for three types of VE: non-specific VE against any RVGE; genotype-specific VE against specific genotypes; and RV1-typic VE against genotypes homotypic, partially heterotypic, or fully heterotypic with the RV1 G1 and P[8] antigens. Models were adjusted for oral poliovirus vaccination concomitant with RV1 vaccination and the country’s child mortality stratum. Results A total of 87,644 infants from 22 countries in the Americas, Europe, Africa, and Asia were included in analysis. VE against severe RVGE was 91% (95% confidence interval (CI): 87-94%). Genotype-specific VE ranged from 96% (95% CI: 89-98%) against homotypic G1P[8] to 71% (95% CI: 43-85%) against fully-heterotypic G2P[4]. VE against severe RVGE caused by partially heterotypic genotypes (92% (95% CI: 84-96%)) was similar to VE against the homotypic genotype, but VE against fully heterotypic genotypes was lower (83% (95% CI: 67-91%)). VE against any-severity RVGE was 82% (95% CI: 75-87%). Genotype-specific VE estimates against any-severity RVGE ranged from 94% (95% CI: 86-97%) against G1P[8] to 63% (95% CI: 41-77%) against G2P[4]. VE against any-severity RVGE was lower (83% (95% CI: 72-90%) against partially heterotypic genotypes, but lowest (63% (95% CI: 40-77%)) against fully heterotypic genotypes. Conclusion RV1 VE is diminished against fully heterotypic genotypes including G2P[4]. Disclosures Benjamin Lopman, PhD, Epidemiological Research and Methods, LLC: Advisor/Consultant.