Background. Rotavirus vaccine efficacy is lower in low-income countries than in high-income countries. Rwanda was one of the first low-income countries in sub-Saharan Africa to introduce rotavirus vaccine into its national immunization program. We sought to evaluate rotavirus vaccine effectiveness (VE) in this setting. Methods. VE was assessed using a case-control design. Cases and test-negative controls were children who presented with a diarrheal illness to 1 of 8 sentinel district hospitals and 10 associated health centers and had a stool specimen that tested positive (cases) or negative (controls) for rotavirus by enzyme immunoassay. Due to high vaccine coverage almost immediately after vaccine introduction, the analysis was restricted to children 7–18 weeks of age at time of rotavirus vaccine introduction. VE was calculated as (1 – odds ratio) × 100, where the odds ratio was the adjusted odds ratio for the rotavirus vaccination rate among case-patients compared with controls. Results. Forty-eight rotavirus-positive and 152 rotavirus-negative children were enrolled. Rotavirus-positive children were significantly less likely to have received rotavirus vaccine (33/44 [73%] unvaccinated) compared with rotavirus-negative children (81/136 [59%] unvaccinated) (P = .002). A full 3-dose series was 75% (95% confidence interval [CI], 31%–91%) effective against rotavirus gastroenteritis requiring hospitalization or a health center visit and was 65% (95% CI, −80% to 93%) in children 6–11 months of age and 81% (95% CI, 25%–95%) in children ≥12 months of age. Conclusions. Rotavirus vaccine is effective in preventing rotavirus disease in Rwandan children who began their rotavirus vaccine series from 7 to 18 weeks of age. Protection from vaccination was sustained after the first year of life.