Porcine reproductive and respiratory syndrome virus (PRRSV) replicates primarily in pulmonary alveolar macrophages (PAMs) and the resulting lung damage is influenced by strain virulence. To better understand the pathogenesis of PRRSV infection, we performed a longitudinal study of the PAM population and lung cytokines in specific pathogen-free pigs infected either with the highly pathogenic Lena strain or with the low pathogenic Finistere strain in comparison to uninfected pigs. Bronchoalveolar lavage fluid (BALF) and blood were collected to follow viral, cellular and cytokine changes in lung with respect to clinical signs and systemic events. Compared to Finistere-infected pigs, Lena-infected pigs exhibited more severe clinical signs and 10- to 100-fold higher viral loads in BALF and blood. Similarly, they showed an earlier drop in BALF cell viability and phagocytic activity along with a decrease in the macrophage count. From 8 to 15 days post-infection (dpi), monocytes increased both in BALF and blood from Lena-infected pigs. BALF and blood showed contrasting cytokine patterns, with low increase of IFN-α and TNF-α levels and high increase for IL-1α and IL-8 in BALF after Lena-infection. In contrast, in the blood, the increase was marked for IFN-α and TNF-α but limited for IL-1β and IL-8. Down-regulation of PAM functions combined with inflammatory cytokine and monocyte recruitment may promote lung pathogenesis and virus replication in PRRSV infections with the highly pathogenic Lena strain. In contrast, the low pathogenic Finistere strain showed prolonged viral replication in lung, possibly related to the weak IFN-γ response.