During the 20th century, significant strides were made in curtailing the burden of childhood diarrhea, including advances in vaccine research, the advent of antibiotics, improved water and sanitation, and expanded access to health information across the globe. Despite this progress, today diarrhea ranks second only to pneumonia as a leading cause of mortality in children under five years, with a disproportionate burden of 90% of diarrheal deaths in South Asia and Sub-Saharan Africa. Additionally, substantial morbidity due to diarrhea persists in young children, with more than 45 million disability-adjusted life years (DALYs) lost due to diarrhea in 2015. Long-term consequences of childhood diarrhea include undernutrition, impaired gut function, altered gut microbiota, and compromised cognitive development. The 21st century presents an opportunity to eliminate the health disparity affecting millions of children suffering disproportionately from preventable diarrheal diseases. Recent advances in molecular laboratory technology have enabled detailed assessment of diarrheal burden and etiology, illuminating the highest burden pathogens for focused interventions. Among the top diarrheal pathogens, rotavirus (RV) is the leading cause of diarrhea-attributable death in the first year of life. While we have vaccines against RV, these vaccines consistently underperform in low and middle-income countries (LMICs) with efficacy of 18% to 61% compared to > 85% efficacy in high income countries. Reasons for rotavirus vaccine underperformance remain unclear, and no vaccines are available for other high burden diarrheal pathogens. This requires consideration of complementary and alternative interventions for diarrhea prevention. To assess factors related to rotavirus vaccine performance, we enrolled a 700-infant birth cohort in an urban slum of Dhaka, Bangladesh, in the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study: a randomized controlled trial of a 2-dose monovalent oral rotavirus vaccine (RV1). With a primary outcome of any rotavirus diarrhea (RVD) post-vaccination to one year, we conducted biweekly home-based diarrhea surveillance with rotavirus antigen detection in diarrheal stools by ELISA. We found RV1 efficacy of 51% (95% CI 33.8–63.7) in per protocol analysis. Importantly, among 12 explanatory variables tested for association with RVD, serum zinc concentration (SZC) in infants at week 18 associated with risk of RVD up to one year (OR 0.77, 95% CI 0.66–0.91), independent of vaccination status. This finding led to broader investigation of the relationship between zinc status and diarrhea in the PROVIDE cohort. Among 577 PROVIDE infants, 16.5% were zinc deficient at week 18 (SZC < 65μg/dL). By logistic regression, zinc deficient infants had increased odds of diarrhea in the first year of life compared to zinc replete infants (OR 2.76, 95% CI 1.08–7.04), and they were nearly 4 times more likely to have diarrhea of viral etiology (OR 3.94, 95% CI 1.55–10.03). Furthermore, in Kaplan Meier analysis we found a strong correlation between zinc deficiency and time to first episode of viral diarrhea (median survival 27 vs 33 weeks in zinc deficient vs non-deficient infants, p <0.0001), with zinc deficient infants at 55% greater risk of viral diarrhea (HR 1.55, 95% CI 1.21 – 1.99). Our results indicate further consideration of zinc as a critical and modifiable co-factor in ameliorating the burden of childhood viral diarrhea. Carefully designed trials of zinc supplementation interventions could determine whether zinc may fill the gap in protection against childhood viral diarrhea, and inquiries into the zinc-diarrhea molecular pathway could elucidate mechanisms for focused development of future interventions.