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Pancreatic cancer is often fatal, and further effective therapeutic options are needed. This study was designed to assess whether the replication-restricted herpes simplex virus, G207, was effective in killing human pancreatic cancer cells in vitro. G207, a multimutated strain of herpes simplex virus type 1 carrying lacZ reporter gene, is capable of efficient cytolytic growth in many dividing cells, including certain tumor cells, but not in nondividing cells. Three human pancreatic cell lines, AsPC-1, MIA PaCa-2, and BxPC-3, were infected with G207 at different multiplicities of infection. After 24 hours, expression of the lacZ reporter gene was tested using a histochemical X-gal assay. In addition, cell lines were infected with G207 for 24 to 48 hours; then the virus obtained from cell pellets and media supernatant was used to infect Vero cells to obtain G207 titers by plaque assay. To assess whether increasing viral immediate early gene expression would improve cytolysis and virus production, similar experiments were performed with the addition of 0.5 mmol/L of hexamethylene bisacetamide (HMBA) 1 hour after viral infection. Finally, MTS cell viability assays were performed to measure viable cells at 24 to 96 hours post infection. The X-gal assay data revealed a viral dose-dependent b-galactosidase expression, indicating G207 infectivity and expression of the lacZ reporter gene. Plaque assays demonstrated a viral dose-dependent increase in plaque formation, indicating viral production from all three cell lines. In addition, HMBA data indicated a modest increase in viral production. The MTS assay data indicated a dose-dependent cytotoxicity for G207 in the cell lines tested. G207 infects, replicates in, and is cytotoxic to the above-listed human pancreatic cell lines in vitro and warrants therapeutic evaluation in models of pancreatic cancer.