BACKGROUND: We conducted a national impact evaluation of routine rotavirus vaccination on childhood diarrhea in Peru, accounting for potential modifying factors. METHODS: We utilized a dataset compiled from Peruvian governmental sources to fit negative binomial models investigating the impact of rotavirus vaccination, piped water access, sewerage access and poverty on the rate of diarrhea clinic visits in children under 5 years old in 194 Peruvian provinces. We considered the interaction between these factors to assess whether water access, sanitation access, or poverty modified the association between ongoing rotavirus vaccination and childhood diarrhea clinic visits. We compared the "pre-vaccine" (2005-2009) and "post-vaccine" (2010-2015) eras. RESULTS: The rate of childhood diarrhea clinic visits was 7% [95% confidence interval (CI): 3%-10%] lower in the post-vaccine era compared to the pre-vaccine era, controlling for long-term trend and El Niño seasons. No impact of rotavirus vaccination was identified in provinces with the lowest access to piped water (when <40% of province households had piped water) or in the lowest category of sewerage (when <17% of province households had a sewerage connection). Accounting for long-term and El Niño trends, the rate of childhood diarrhea clinic visits was lower in the post-vaccine era by 7% (95% CI: 2%-12%), 13% (95% CI: 7%-19%) and 15% (95% CI: 10%-20%) in the second, third and fourth (highest) quartiles of piped water access, respectively (compared to the pre-vaccine era); results for sewerage access were similar. CONCLUSION: Improved water/sanitation may operate synergistically with rotavirus vaccination to reduce childhood clinic visits for diarrhea in Peru.