Acute rheumatic fever (ARF) is a serious autoinflammatory disease that develops after a Streptococcus A (StrepA) infection in susceptible children. The rates of ARF in Indigenous children in New Zealand and Australia are amongst the highest in the world but drivers for the disease are poorly understood. Repeat exposures to StrepA are thought to “prime” the immune system for an autoimmune reaction. However, it is not known if children who develop ARF experience more StrepA exposures compared to those who do not, or if an underlying susceptibility is the main driver for disease development. The aim of this study is to answer this fundamental question by exploiting serum memory and the fact that humoral responses to StrepA can persist for decades. We have developed methodology that allows retrospective mapping of StrepA exposures in patient sera based on the emm-type of previously infecting strains. Emm-typing is the most widely used epidemiological typing tool for defining StrepA strain diversity. A panel of 50-mer peptides corresponding to the hypervariable region of the GAS M-protein (the emm-type encoding region) was designed and synthesised that covers >90% and >97% of strain emm-types and cluster types, respectively, prevalent in New Zealand. Sera from 30 ARF cases and 30 highly matched controls collected as part of the recently completed Rheumatic Fever Risk Factors study conducted in New Zealand (HDEC 14/NTA/53/AM02) were screened for M-type specific responses in immunoassays using the large peptide panel. The serum reactivity profiles were compared between each highly matched case/control pair. Wilcoxon matched-pairs signed ranked test showed a significant increase in the number of HVR reactivities in the ARF cases compared with controls (median reactivity 11 vs 4, p = 0.0001). The significant increase in M-type specific reactivity observed in ARF sera suggests children who develop ARF are “primed” for disease via increased StrepA exposures. This has important implications for the design of future disease prevention strategies.