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Background Scrub typhus, caused by Orientia tsutsugamushi, an obligate intracellular gram-negative bacterium, along with hemorrhagic fever with renal syndrome (HFRS), caused by hantaviruses, are natural-focus infectious diseases prevalent in Shandong Province, China. Both diseases have similar clinical manifestations in certain disease stages and similar epidemic seasons, which has caused difficulties for physicians in distinguishing them. The aim of this study was to investigate whether misdiagnosis of scrub typhus as HFRS occurred in patients in Shandong Province. Methods Serum samples (N = 112) of clinically suspected HFRS patients from 2013 to 2014 in Shandong Province were analyzed with enzyme-linked immunosorbent assay (ELISA) for antibodies to both hantavirus and Orientia tsutsugamushi. Results ELISA showed that 56.3% (63/112) and 8.0% (9/112) of clinically suspected HFRS patients were IgM antibody positive to hantavirus and O. tsutsugamushi, respectively. Among the hantavirus IgM antibody positive patients, 7.9% (5/63) were also IgM antibody positive to O. tsutsugamushi. Among the hantavirus IgM antibody negative sera, 8.2% (4/49) of sera were positive to O. tsutsugamushi. Conclusions We concluded that some scrub typhus patients were misdiagnosed as HFRS and co-infection of scrub typhus and HFRS might exist in China. Due to the different treatments for scrub typhus and HFRS, physicians should carefully differentiate between scrub typhus and HFRS and consider administering anti-rickettsia antibiotics if treatment for HFRS alone does not work., Author summary Scrub typhus is caused by O. tsutsugamushi and hemorrhagic fever with renal syndrome (HFRS) is caused by hantavirus. Both diseases have similar manifestations and have their peak epidemic season in the fall, which makes their clinical differentiation difficult to be differentiated from each other clinically. In this study, we found that scrub typhus was indeed misdiagnosed as HFRS and co-infection of O. tsutsugamushi and hantaviruses might exist in China. Owing to different treatments of HFRS and scrub typhus, physicians need pay attention to differentiate them; identify co-infection of HFRS and scrub typhus; and consider administering antibiotics if antiviral treatment alone does not work.