Objective To test the hypothesis that cases of Kawasaki disease within a temporal cluster have a similar pattern of host response that is distinct from cases of Kawasaki disease in different observed clusters and randomly constructed clusters. Study design We designed a case-control study to analyze 47 clusters derived from 1332 patients with Kawasaki disease over a 17-yr. period (2002-2019) from a single clinical site and compared the cluster characteristics with two control groups of synthetic KD clusters. We defined a “true” KD cluster as at least 5 patients within a 7-day moving window. The observed and synthetic KD clusters were compared with respect to demographic and clinical characteristics and median values for standard laboratory data using univariate analysis and a multivariate, Rotated Empirical Orthogonal Function Analysis (REOFs). Results In a univariate analysis, the median values for age, coronary artery Z score, white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and age-adjusted hemoglobin for several of the true KD clusters exceeded the 95th percentile for the two synthetic clusters. REOFs revealed distinct patterns of demographic and clinical measures within clusters. Conclusions Cases of Kawasaki disease within a cluster were more similar with respect to demographic and clinical features, and levels of inflammation than would be expected by chance. These observations suggest that different triggers and/or different intensity of exposures result in clusters of cases of Kawasaki disease that share a similar response pattern. Analyzing cases within clusters or cases who share demographic and clinical features may lead to new insights into the etiology of KD.