Pregnant women can experience high mortality, high rates of abortion, and severe pneumonia when infected with pandemic influenza viruses. In this context, the severity of the 2009 pandemic H1N1 influenza virus compared with seasonal H1N1 influenza virus is not clear. Presently, in a mouse model of pregnancy, the 2009 pandemic H1N1 influenza virus killed up to 60% of pregnant mice and caused abortion in up to 40%, whereas a circulating seasonal H1N1 influenza virus did not cause any deaths or abortions. Higher viral titers and levels of inflammatory cytokines and chemokines such as interleukin (IL)-1α, IL-6, granulocyte colony-stimulating factor, RANTES, monocyte chemotactic protein, and KC (CXCL1), were detected in the lungs of pregnant mice infected with the 2009 pandemic H1N1 influenza virus, compared with the seasonal H1N1 influenza virus. The results of our study with pregnant mice suggest that the observed higher pathogenesis in pregnant women infected with the 2009 pandemic H1N1 influenza virus than the seasonal H1N1 influenza virus may be due to higher viral replication, elevated induction of inflammatory chemokines, and reduced progesterone.