© 2019 The Author(s). Background: Evidence remains contradictory regarding second-line therapy in patients with Kawasaki disease (KD) refractory to initial intravenous immunoglobulin (IVIg). The objective of this study aims to evaluate the efficacy and safety of three treatments [i.e. a second IVIg infusion, methylprednisolone (IVMP), and infliximab (IFX)] in patients with refractory KD. Methods: A systematic search of PubMed, Embase, Cochrane, and ClinicalTrials.gov using predefined MeSH terms was performed from 1990 through 2017. Relevance screening was performed by two independent reviewers. Inclusion criteria included English-only, original clinical data. Eight studies met the inclusion criteria. Fever resolution, coronary lesions, and adverse event outcomes were extracted and pooled for analysis. Results: Of the 388 patients included from the 8 studies analyzed, a majority received a second IVIg dose (n = 263, 68%). Fever resolution was comparable between IVIg (72%) and IVMP (73%). IFX (88%) significantly increased fever resolution by approximately 20% compared to IVIg re-dose (RR 1.2; [95% CI: 1.1-1.4]; p = 0.03) and IVMP (RR 1.2; [95% CI: 1.0-1.5]; p = 0.04). Clinical significance of differences in coronary outcomes remains unclear. Conclusions: This combined analysis was limited due to variability in design and data reporting methods between the studies and risk of bias. In the absence of a clinical trial, IFX monotherapy as second-line treatment should be considered in patients who fail to respond to initial IVIg. This conclusion is based on a systematic review of the literature with pooled outcome data analysis suggesting IFX is more effective in fever resolution compared to a second IVIg dose and IVMP.