Vaccination against porcine reproductive and respiratory syndrome virus (PRRSV) results often in limited protection. Understanding host immune responses and pathogenesis elicited by different PRRSV strains could help to develop more efficacious vaccines. Differences in host response between the European subtype 3 strain Lena and subtype 1 strains Belgium A and Lelystad-Ter Huurne (LV) were examined in several studies and “meta-analyses” results across studies will be presented. Characteristic of infections with strain Lena, compared to strains Belgium A and LV, are fever, clinical symptoms, a systemic inflammatory response, higher virus titres in serum, differences in leukocyte populations in blood, lower numbers of IFN-γ secreting cells in blood, and a delayed antibody response against a non-related immunization. In the lungs, infection with strain Lena induce more severe acute pathology with an proinflammatory response and an influx of neutrophils and monocytes in bronchoalveolar lavage fluid (BALF). However, after a few weeks, all strains induce an increased percentage of cytotoxic T cells and higher levels of IFN-γ producing cells in BALF. We hypothesized that the stronger early inflammatory response of the Lena strain contributed to the observed faster clearance of virus after infection and better protection against reinfection. In a comparative study, this hypothesis was tested. Pigs were infected with strains Lena or LV and homologous challenged after 46 days. Challenge infection resulted in both groups in complete protection , with no viraemia, clinical symptoms or viral RNA in tissues. After the challenge, a boost in antibody levels in pigs infected with homologous strains mounted rapidly and IFN-γ ELISPOT assays showed comparable responses between Lena and LV, when cells were homologous stimulated. However, clear differences between the strains in levels of neutralizing antibodies and IFN-γ SC were observed when the assays were performed with heterologous virus. In conclusion, although, there are clear differences in immunological, clinical and virological responses after infection, with stronger inflammatory response for strain Lena-infected pigs, there were no differences observed in protection against homologous challenge. Whether this is also true for heterologous challenges needs further research.