Abstract. Horses were inoculated with Vesicular stomatitis New Jersey and Indiana viruses by routes simulating contact and vector transmission. Clinical signs, lesions, antibody development, viral shedding and persistence, and viremia were monitored. Horses were infected with both viruses by all routes as confirmed by seroconversion. Salivation, primary lesions at inoculation sites, and secondary oral lesions were the most common clinical findings. Viral shedding was most often from the oral cavity, followed by the nasal cavity; titers were highest from oral cavity samples. Virus was rarely isolated from the conjunctival sac and never from feces or blood. Development of neutralizing antibody coincided with cessation of lesion development and detection of virus by isolation. Circulating virus-specific IgM, IgG, IgA, and neutralizing antibodies developed in most animals postinoculation (PI) days 6 to 12, depending on the route of inoculation. At postmortem (PI days 12 to 15), lesions were healing, were not vesicular, and did not contain detectable virus by isolation, reverse transcriptase polymerase chain reaction, or immunohistochemistry. Numerous infiltrating lymphocytes and plasma cells suggested that lesion resolution was partially due to local immunity. Detection of viral RNA from tonsil and lymph nodes of head at necropsy suggests that these tissues play a role in the pathogenesis of the disease; molecular techniques targeting these tissues may be useful for confirming infection in resolving stages of disease. The routes of inoculation used in this study reflect the diversity of transmission routes that may occur during outbreaks and can be used to further study contact and vector transmission, vaccine development, and clarify pathogenesis of the disease in horses.