The aim of this systematic review was to evaluate the efficacy of amino acid-based formulas (AAF) in patients with cow's milk allergy (CMA). Studies were identified using electronic databases and bibliography searches. Subjects eligible for inclusion were patients of any age with CMA or symptoms suggestive of it. Comparisons of interest were AAF vs. extensively hydrolysed formula (eHF), AAF vs. soy-based formula (SF) and AAF vs. cow's milk or cow's milk-based formula. Outcomes of interest were gastrointestinal (GI), dermatological, respiratory and behavioural symptoms as well as growth. A total of 20 studies [three head-to-head randomized controlled trials (RCTs), three cross-over challenge RCTs, seven clinical trials (CTs) and seven case reports (CRs)] were included in the review. In infants with confirmed or suspected CMA, the use of an AAF was shown to be safe and efficacious. Findings from RCT comparisons of AAF with eHF showed that both formulas are equally efficacious at relieving the symptoms of CMA in confirmed or suspected cases. However, infants in specific subgroups (e.g. non-IgE mediated food-induced gastro-enterocolitis-proctitis syndromes with failure to thrive, severe atopic eczema, or with symptoms during exclusive breastfeeding) were more likely overall to benefit from AAF, as intolerance to eHF may occur. In such cases, symptoms persisting despite eHF feeding usually remit on AAF, and catch-up growth may be seen. Meta-analysis of the findings was not possible due to lack of homogenous reporting of outcomes in the original trials. This systematic review shows clinical benefit from use of AAF in both symptoms and growth in infants and children with CMA who fail to tolerate eHF. Further studies are required to determine the relative medical or economic value of initial treatment with AAF in infants at high risk of eHF intolerance.