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Background Global cholera control efforts rely heavily on effective water, sanitation, and hygiene (WASH) interventions in cholera-endemic settings. Methods Using data from a large, randomized controlled trial of oral cholera vaccine conducted in Kolkata, India, we evaluated whether natural variations in WASH in an urban slum setting were predictive of cholera risk. From the control population (n = 55 086), baseline WASH data from a randomly selected "training subpopulation" (n = 27 634) were analyzed with recursive partitioning to develop a dichotomous ("better" vs "not better") composite household WASH variable from several WASH features collected at baseline, and this composite variable was then evaluated in a mutually exclusive "validation population" (n = 27 452). We then evaluated whether residents of better WASH households in the entire population (n = 55 086) experienced lower cholera risk using Cox regression models. Better WASH was defined by a combination of 4 dichotomized WASH characteristics including safe source of water for daily use, safe source of drinking water, private or shared flush toilet use, and always handwashing with soap after defecation. Results Residence in better WASH households was associated with a 30% reduction in risk of cholera over a 5-year period (adjusted hazard ratio, 0.70 [95% confidence interval,.49–.99]; P =.048). We also found that the impact of better WASH households on reducing cholera risk was greatest in young children (0–4 years) and this effect progressively declined with age. Conclusions The evidence suggests that modest improvements in WASH facilities and behaviors significantly modify cholera risk and may be an important component of cholera prevention and elimination strategies in endemic settings. Clinical Trials Registration. NCT00289224. [ABSTRACT FROM AUTHOR]