Infantile Colic: When to Suspect Cow’s Milk Allergy

Background/Objectives: Worldwide, an estimated 20–30% of infants suffer from infant colic (IC), with excessive crying and unsettled behavior, during the first three months of life. These infants are often referred for a medical evaluation, but the pathogenesis of IC remains poorly understood. The aim of this narrative review is to critically appraise the available literature regarding the relation between IC and cow’s milk allergy (CMA). Methods: A literature search using the search strings cow’s milk allergy MeSH Terms OR food allergy MesH Terms AND colic MeSH Terms OR crying MeSH Terms, limited to the English language, from inception to 15 June 2025, resulted in the identification of 135 articles. Of these, 18 clinical trials assessed the effect of a cow’s milk elimination diet on IC. Results: The role of CMA in IC in the absence of other allergic manifestations remains uncertain. However, when standard treatment of infant colic has failed and when other allergic symptoms are present, CMA may be considered. A diagnostic elimination diet which includes a 2–4-week trial of maternal cow’s milk elimination in breastfed infants or an extensively hydrolyzed cow’s milk or hydrolyzed rice formula should be performed. If the elimination diet results in a significant decrease in symptoms, reintroduction of cow’s milk protein into the diet is mandatory to fulfill the diagnostic criteria of CMA. Conclusions: Considering the limited current evidence, future research should prioritize large well-designed clinical trials with a focus on investigating CMA in colicky breastfed and formula-fed infants.