The extracellular matrix (ECM) acts as a survival factor for cells, as shown in this study. Human endothelial cells (HUVECs) undergo programmed cell death (PCD) when not in contact with the ECM, as evidenced by cell shrinkage, membrane blebbing, nuclear fragmentation, DNA degradation, and the expression of the PCD-specific gene TRPM-2. PCD was blocked when cells were plated on an integrin β1 antibody, but not on antibodies to HLA or VCAM-1, suggesting integrin-mediated signals are required for cell survival. Treatment with the tyrosine phosphatase inhibitor sodium orthovanadate also blocked PCD, indicating that tyrosine phosphorylation is involved. Other cell types also showed PCD when deprived of ECM adhesion, suggesting the ECM functions as a survival factor for many cell types beyond endothelial cells. The study highlights the role of integrins in signaling pathways that maintain cell viability and the importance of ECM interactions in preventing PCD. The findings suggest that the ECM, through integrin signaling, regulates cell survival, similar to growth factors and hormones. The results also imply that the ECM's role in cell survival is widespread, with implications for development, organ regression, and cancer metastasis.The extracellular matrix (ECM) acts as a survival factor for cells, as shown in this study. Human endothelial cells (HUVECs) undergo programmed cell death (PCD) when not in contact with the ECM, as evidenced by cell shrinkage, membrane blebbing, nuclear fragmentation, DNA degradation, and the expression of the PCD-specific gene TRPM-2. PCD was blocked when cells were plated on an integrin β1 antibody, but not on antibodies to HLA or VCAM-1, suggesting integrin-mediated signals are required for cell survival. Treatment with the tyrosine phosphatase inhibitor sodium orthovanadate also blocked PCD, indicating that tyrosine phosphorylation is involved. Other cell types also showed PCD when deprived of ECM adhesion, suggesting the ECM functions as a survival factor for many cell types beyond endothelial cells. The study highlights the role of integrins in signaling pathways that maintain cell viability and the importance of ECM interactions in preventing PCD. The findings suggest that the ECM, through integrin signaling, regulates cell survival, similar to growth factors and hormones. The results also imply that the ECM's role in cell survival is widespread, with implications for development, organ regression, and cancer metastasis.