Non-adherence in clinical trials affects safety and efficacy determinations. Predictors of non-adherence in pediatric acute illness trials are unknown. We sought to examine predictors of non-adherence in a multicenter randomized trial of 971 children with acute gastroenteritis receiving a 5-day oral course of Lactobacillus rhamnosus GG or placebo. Adherence, defined as consuming all doses of the product, was reported by the parents and recorded during daily follow-up contacts. Of 943 patients with follow-up data, 766 (81.2%) where adherent. On multivariate analysis older age (OR 1.19; 95%CI: 1.00-1.43), increased vomiting duration (OR 1.23; 95% CI: 1.05-1.45), higher dehydration score (OR 1.23, 95% CI: 1.07-1.42) and hospitalization following ED discharge (OR 4.16, 95% CI: 1.21, 14.30) were factors associated with non-adherence; however those with highest severity scores were more likely to adhere (OR 0.87, 95% CI: 0.80-0.95). These data may inform strategies and specific targets to maximize adherence in future pediatric trials.