Background: Intravenous (IV) acetaminophen is increasingly used around the world for pain control for a variety of indications. However, it is unclear whether IV administration offers advantages over oral administration. Objective: To identify, summarize, and critically evaluate the literature comparing analgesic efficacy, safety, and pharmacokinetics for IV and oral dosage forms of acetaminophen. Data Sources: A literature search of the PubMed, Embase, and International Pharmaceutical Abstracts databases was supplemented with keyword searches of Science Direct, Wiley Library Online, and Springer Link databases for the period 1948 to November 2014. The reference lists of identified studies were searched manually. Study Selection and Data Extraction: Randomized controlled trials comparing IV and oral dosage forms of acetaminophen were included if they assessed an efficacy, safety, or pharmacokinetic outcome. For each study, 2 investigators independently extracted data (study design, population, interventions, follow-up, efficacy outcomes, safety outcomes, pharmacokinetic outcomes, and any other pertinent information) and completed risk-of-bias assessments. Data Synthesis: Six randomized clinical trials were included. Three of the studies reported outcomes pertaining to efficacy, 4 to safety, and 4 to pharmacokinetics. No clinically significant differences in efficacy were found between the 2 dosage forms. Safety outcomes were not reported consistently enough to allow adequate assessment. No evidence was found to suggest that increased bioavailability of the IV formulation enhances efficacy outcomes. For studies reporting clinical outcomes, the results of risk-of-bias assessments were largely unclear. Conclusions: For patients who can take an oral dosage form, no clear indication exists for preferential prescribing of IV acetaminophen. Decision-making must take into account the known adverse effects of each dosage form and other considerations such as convenience and cost. Future studies should assess multiple-dose regimens over longer periods for patients with common pain indications such as cancer, trauma, and surgery.