CONTEXT Discovering new interventions to improve neurodevelopmental outcomes is a priority; however, clinical trials are challenging and methodological issues may impact the interpretation of intervention efficacy. OBJECTIVES Characterize the proportion of infant neurodevelopment trials reporting a null finding and identify features that may contribute to a null result. DATA SOURCES The Cochrane library, Medline, Embase, and CINAHL databases. STUDY SELECTION Randomized controlled trials recruiting infants aged <6 months comparing any “infant-directed” intervention against standard care, placebo, or another intervention. Neurodevelopment assessed as the primary outcome between 12 months and 10 years of age using a defined list of tools. DATA EXTRACTION Two reviewers independently extracted data and assessed quality of included studies. RESULTS Of n = 1283 records screened, 21 studies (from 20 reports) were included. Of 18 superiority studies, >70% reported a null finding. Features were identified that may have contributed to the high proportion of null findings, including selection and timing of the primary outcome measure, anticipated effect size, sample size and power, and statistical analysis methodology and rigor. LIMITATIONS Publication bias against null studies means the proportion of null findings is likely underestimated. Studies assessing neurodevelopment as a secondary or within a composite outcome were excluded. CONCLUSIONS This review identified a high proportion of infant neurodevelopmental trials that produced a null finding and detected several methodological and design considerations which may have contributed. We make several recommendations for future trials, including more sophisticated approaches to trial design, outcome assessment, and analysis.