Swine influenza viruses (SIV) of the hemagglutinin subtype 1 (H1) isolated from the United States (U.S.) have not been well-characterized in the natural host. An increase in the rate of mutation and reassortment has occurred in SIV isolates from the U.S. since 1998, including viruses belonging to the H1 subtype. Two independent animal studies were done to evaluate and compare the pathogenesis of 10 SIV isolates dating from 1930 to currently circulating isolates. In addition, the hemagglutinin and neuraminidase genes of each isolate were sequenced for genetic comparison, and serological cross-reactivity was evaluated using all sera and virus combinations in hemagglutination inhibition and serum neutralization assays. Statistically significant differences in percentage of pneumonia and virus titers in the lung were detected between isolates, with modern isolates tending to produce more severe disease, have more virus shedding and higher viral titers. However, nasal shedding and virus titers in the lung were not always correlated with one another or lung lesions. Serologically, the classic historical H1N1 viruses tended to have better cross-reaction between historical sera and antigens, with moderate to good cross-reactivity with modern viral antigens. However, the modern sera were less reactive with historical viruses. Modern viruses tended to have less consistent cross-reactivity within the modern group. Overall, H1 isolates collected over the last 75 years from the U.S. pig population exhibit considerable variability in pathogenicity. There appears to be an increase in genetic and antigenic diversity coincident with the emergence of the swine triple reassortant H3N2 in 1998.