Background. Previously, we demonstrated that neuroblastoma cells cocultured with hepatocytes are protected from apoptosis, while apoptosis is upregulated in the hepatocytes. The mechanisms responsible for these findings are unknown. We hypothesize that caspase 3, a cysteine protease central to the apoptotic pathway, will be altered in this coculture model that simulates metastatic neuroblastoma. Methods. Control human neuroblastoma cells and liver cells are plated in standard media. For the study group, a noncontact, coculture system is used. Hepatocytes are plated on cell culture inserts, placed above a growing layer of neuroblastoma cells, and incubated. Activated caspase 3 is measured after 1, 2, 3, or 4 days. Results. Activated caspase 3 levels are significantly decreased in the cocultured neuroblastoma cells on days 2, 3, and 4. Conversely, cocultured hepatocytes have a significant increase in caspase 3 activation at all time periods, with the largest difference seen after 1 day in coculture. Conclusions. The capacity for neuroblastoma to differentially alter caspase 3 activation may provide a significant survival advantage for the neuroblastoma cells in metastatic environments. Understanding the mechanisms for this altered regulation may lead to improved and better targeted therapy for this malignancy. © 2002 Elsevier Science (USA).