Syrian hamsters, strain MHA/Lak, are susceptible to intraperitoneal infection with Pichinde virus and die from an overwhelming viremia. We have studied the ability of a vaccinia-Pichinde recombinant virus expressing amino acids 51-561 of the viral nucleoprotein (VVNP51-561) to protect from lethal Pichinde virus infection. Priming with VVNP51-561 significantly delayed mortality and increased final survival outcome after challenge with 2 x 10(3) pfu of Pichinde virus. This protection was not complete compared to priming with Pichinde virus in the footpad, which was not lethal and provided 100% protection. At a higher challenge dose of Pichinde virus, 2 x 10(4) pfu, immunization with VVNP51-561 delayed mortality but did not increase final survival. The partial protection correlated with an early but not late reduction in infectious virus in serum, kidney and liver, and infectious centers in the spleen. Thus the immune response generated by VVNP51-561 could initially control the infection, effectively reducing the virus inoculum. As the infection proceeded, virus replication could not be limited resulting in death in some hamsters. The partial protection did not appear to be mediated by anti-viral antibodies since these were not detected in the serum of VVNP56-561-immunized hamsters. This finding appears to support the hypothesis that in many arenavirus infections cellular immunity is central to viral clearance and protection from reinfection.