This study investigated whole-cell oral cholera vaccine (kOCV) single-dose effectiveness and transmission dynamics of Vibrio cholerae through 4 years of epidemiological and genomic surveillance in Democratic Republic of the Congo (DRC). Whole genome sequencing was performed on clinical and water V. cholerae strains from 200 patient households and found annual bimodal peaks of V. cholerae clade AFR10e. 1154 diarrhea patients were enrolled with 342 culture confirmed cholera patients. A large clonal cholera outbreak occurred 18 months after a kOCV campaign of >1 million doses of Euvichol-Plus, likely because of low vaccine coverage in informal settlements (9%). Clinical and water V. cholerae strains in the same household were more closely related than different households suggesting both person-to-person and water-to-person transmission. Single-dose kOCV vaccine effectiveness in the first 24 month after vaccination was 56.9% (95% CI: 18.6%-77.2%), suggesting a single-dose provided modest protection against medically attended cholera during the 24 months post-vaccination.