Sera from sequentially bled nephropathia epidemica patients (acute-phase, convalescent-phase, and 2-year sera) and sera from 10 to 20 years postinfection were examined by immunoglobulin G (IgG) subclass-specific ELISAs for reactivities against each of the Puumala virus structural proteins (N, G1, and G2). IgG1 was found to be the dominating antiviral subclass, and most of the patients had IgG1 directed to all three structural proteins at all times with a continuous increase over time. IgG2 to the three viral proteins was detected in very low amounts in only a few of the samples. All of the serially bled patients developed IgG3 against each of the proteins, but the responses against the different viral components varied; anti-N- and anti-G1-specific IgG3 showed a peak in the convalescent-phase samples, while the anti-G2 IgG3 response was highest in the acute-phase sera. Eight of ten serially bled patients developed specific IgG4. The IgG4 responses showed similar patterns against all three viral proteins with very low optical density values in the acute- and convalescent-phase samples, followed by higher optical densities in the sera drawn 2 years after infection. Seven of nine 10-year sera contained virus-specific IgG4. These results support the theory concerning the persistence of Puumala virus or viral antigens several years after infection.