We describe that swine influenza virus-like substitutions T200A and E227A in the hemagglutinin of the 2009 pandemic influenza virus alter its pathogenesis and transmission. Viral replication is increased in mammalian cells. Infected mice show increased disease as measured by weight loss and lethality. Transmission in ferrets is decreased in the presence of both substitutions, suggesting that 200T and 227E HA amino acids are adaptive changes in the HA of swine-origin influenza viruses associated with increased transmission and decreased pathogenesis.