Current guidelines emphasize early introduction to potentially allergenic foods, but the optimal timing, amount, and exposure routes for foods other than peanut are not well-established. Cow's milk is often the first allergenic food introduced through infant formulas. To examine timing of cow's milk protein introduction (CMPI), including interaction with formula supplementation after delivery, in relation to reported cow's milk adverse reactions throughout childhood. Among children in the Boston, Mass-area Project Viva cohort, we assessed timing of CMPI (<2 weeks, 2 weeks-<6 months, ≥6 months) with questionnaires administered in infancy. Outcomes were (1) parent-reported cow's milk adverse reactions via annual questionnaires from age 2 to 13 years (n = 1298) and (2) milk sensitization (n = 505) and IgE-mediated milk allergy (n = 491) at age approximately 8 years. We used multivariable logistic regression models adjusted for parental atopy history, delivery mode, gestational age at delivery, child race, and census tract median household income, and investigated effect modification by ever/never breast-fed status and formula supplementation in the delivery hospital. A total of 32% were introduced to cow's milk protein at age less than 2 weeks, 38% at age 2 weeks to less than 6 months, and 30% at age 6 months or more. Compared with children with CMPI at age less than 2 weeks, children with CMPI at age 6 months or more had a higher risk of cow's milk adverse reaction at age 2 to 5 years (odds ratio, 2.4 [1.2-4.7]). Children given formula after delivery + CMPI at age less than 2 weeks had the lowest risk overall. Among children not given formula after delivery, CMPI at age 2 weeks to 6 months appeared most protective. Results were similar among ever-breast-fed children. Timing of CMPI was not associated with milk sensitization or IgE-mediated milk allergy in mid-childhood. Early, consistent cow's milk exposure appears protective against adverse reactions to cow's milk.