Background Histo-blood group antigens (HBGAs) have been associated with rotavirus vaccine take; but the effect of these HBGAs on rotavirus incidence and risk remains poorly explored in vaccinated populations. Methods Rotavirus-associated acute gastroenteritis (AGE) was assessed in 444 Nicaraguan children followed from birth until 3 years of age. AGE episodes were tested for rotavirus by reverse-transcription quantitative polymerase chain reaction, and saliva or blood was used to determine HBGA phenotypes. Cox proportional hazards models were used to estimate the relative hazard of rotavirus AGE by HBGA phenotypes. Results Rotavirus was detected in 109 (7%) stool samples from 1689 AGE episodes over 36 months of observation between June 2017 and July 2021. Forty-six samples were successfully genotyped. Of these, 15 (35%) were rotavirus vaccine strain G1P[8], followed by G8P[8] or G8P[nt] (11 [24%]) and equine-like G3P[8] (11 [24%]). The overall incidence of rotavirus-associated AGE was 9.2 per 100 child-years, and was significantly higher in secretor than nonsecretor children (9.8 vs 3.5/100 child-years, P = .002). Conclusions The nonsecretor phenotype was associated with decreased risk of clinical rotavirus vaccine failure in a vaccinated Nicaraguan birth cohort. These results show the importance of secretor status on rotavirus risk, even in vaccinated children. Overall incidence of rotavirus-associated AGE in a vaccinated Nicaraguan birth cohort was 9.2/100 child-years. Nonsecretor children had less risk of symptomatic rotavirus infection. These results are important in the context of monitoring effectiveness of rotavirus vaccine trough birth cohort studies.