BACKGROUND Enteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi, remains a major cause of morbidity in low- and middle-income countries, yet burden estimation is challenging in regions without blood culture surveillance. Azithromycin is effective for treating enteric fever, and mass drug administration (MDA) to young children reduces all-cause mortality in sub-Saharan Africa, but its impact on community-level enteric fever burden is unknown. We assessed enteric fever seroincidence in rural Niger and evaluated the effect of biannual azithromycin MDA affected. PRINCIPAL FINDINGS This was a secondary analysis of the MORDOR trial (NCT02048007), a cluster-randomized, placebo-controlled study in 30 communities in Dosso Region, Niger. Children aged 1-59 months received biannual azithromycin or placebo. Dried blood spots collected at baseline (2015) and Year 5 (2020) were tested for IgA and IgG antibodies against Hemolysin E using kinetic ELISA. Seroincidence was estimated using maximum likelihood methods based on antibody kinetics from blood culture-confirmed enteric fever patients. Samples from 1,417 children were analyzed (423 baseline; 994 Year 5). Overall seroincidence approximately doubled from baseline to Year 5, increasing from 68.5 (95% CI 58.0-80.7) to 145.2 (95% CI 132.3-159.3) per 100 person-years in placebo communities and from 74.7 (95% CI 56.5-98.7) to 135.2 (95% CI 112.4-162.6) in azithromycin communities, with no significant difference between arms (difference-in-differences -16.2; 95% CI -53.1-20.8 ). Among children