ABSTRACT: Importance:Acetaminophen (paracetamol) and ibuprofen are the most widely prescribed and available over-the-counter medications for management of fever and pain in children. Despite the common use of these medications, treatment recommendations for young children remain divergent. Objective:To compare acetaminophen with ibuprofen for the short-term treatment of fever or pain in children younger than 2 years. Data Sources:Systematic search of the databases MEDLINE, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials and the trial registers ClinicalTrials.gov and the Australian New Zealand Clinical Trials Registry from inception to March 2019, with no language limits. Study Selection:Studies of any design that included children younger than 2 years and directly compared acetaminophen with ibuprofen, reporting antipyretic, analgesic, and/or safety outcomes were considered. There were no limits on length of follow-up. Data Extraction and Synthesis:Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline, 2 authors independently extracted data and assessed quality. Data were pooled using a fixed-effects method if I2 was less than 50% and using a random-effects method if I2 was 50% or greater. Main Outcomes and Measures:The primary outcomes were fever or pain within 4 hours of treatment onset. Safety outcomes included serious adverse events, kidney impairment, gastrointestinal bleeding, hepatotoxicity, severe soft tissue infection, empyema, and asthma and/or wheeze. Results:Overall, 19 studies (11 randomized; 8 nonrandomized) of 241?138 participants from 7 countries and various health care settings (hospital-based and community-based) were included. Compared with acetaminophen, ibuprofen resulted in reduced temperature at less than 4 hours (4 studies with 435 participants; standardized mean difference [SMD], 0.38; 95% CI, 0.08-0.67; P?=?.01; I2?=?49%; moderate quality evidence) and at 4 to 24 hours (5 studies with 879 participants; SMD, 0.24; 95% CI, 0.03-0.45; P?=?.03; I2?=?57%; moderate-quality evidence) and less pain at 4 to 24 hours (2 studies with 535 participants; SMD, 0.20; 95% CI, 0.03-0.37; P?=?.02; I2?=?25%; moderate-quality evidence). Adverse events were uncommon. Acetaminophen and ibuprofen appeared to have similar serious adverse event profiles (7 studies with 27?932 participants; ibuprofen vs aceteminophen: odds ratio, 1.08; 95% CI, 0.87-1.33; P?=?.50, I2?=?0%; moderate-quality evidence). Conclusions and Relevance:In this study, use of ibuprofen vs acetaminophen for the treatment of fever or pain in children younger than 2 years was associated with reduced temperature and less pain within the first 24 hours of treatment, with equivalent safety.