Nephropathia epidemica (NE) caused by Puumala hantavirus is one type of hemorrhagic fever with renal syndrome (HFRS). There is considerable variability in the clinical severity of NE. Many infections are subclinical but the disease can even be fatal. We questioned whether the wide spectrum in the outcome of NE is dependent, on host-related immunological factors by determining the major histocompatibility complex markers (MHC) in 74 adult patients with NE. Patients with the most severe course of the disease had a very high frequency of HLA B8, C4A*Q0, and DRB1*0301 alleles. HLA B8 was found in all 7 (100%) patients with shock and in 9 of the 13 (69%) patients who required dialysis, versus in only 25 of 74 (34%) in the entire population, and in 14 of 93 (15%) controls. In addition, various other clinical findings pointing to a severe form of NE were found to be associated with these alleles. Interestingly, the same MHC alleles are risk factors for various autoimmune diseases. This is the first study where a certain HLA haplotype is found to be associated with the clinical course of an acute viral disease or acute nephritis.