ABSTRACTScrub typhus, caused byOrientia tsutsugamushiinfection, is one of the main causes of acute febrile illness in the Asian-Pacific region. Although early diagnosis and immediate antibiotic treatment are critical for reducing disease severity and mortality, current diagnostic methods using serological and molecular approaches have some limitations in sensitivity and applicability in clinical laboratories. In this study, we identified and characterizedO. tsutsugamushisurface cell antigen (sca) family genes encoding autotransporter proteins in order to test them as novel diagnostic targets. We evaluated antibody responses against the Sca proteins in scrub typhus patient sera and examined the genetic diversity of these genes in different strains after PCR amplification. Specific antibody responses against ScaA and ScaC were observed in patients with high indirect immunofluorescence assay titers (≥1:640), whereas specific responses against ScaB and ScaE were relatively low. Genetic analysis using genomic DNAs revealed thescagenes to be quite variable among the different strains. In contrast toscaA,scaC, andscaD, which were detected in all of the tested strains,scaBandscaEwere amplified differentially from the different strains, suggesting a differential presence of the genes in the genomes. Among the members of the gene family, the sequence ofscaCis the most highly conserved between the different strains, and the size ofscaDis the most variable due to the presence of different numbers of internal repeat sequences. These results suggest that thescagenes ofO. tsutsugamushimay be valuable targets for use in combination with classical assay methods for scrub typhus diagnosis.