The crossroad between cell death and proliferation is a general target for viral infections because viruses need to obstruct apoptosis to use cells for their own replication. Inducing immunogenic cell death in proliferating cells is also an important aim of anticancer chemotherapy. The C1q-binding proteins calreticulin (CRT) and gC1qR are highly conserved ubiquitous proteins, which are putative targets for viral manipulation and are associated with cancer. Here we show that these proteins form a complex in the cytoplasm as a response to viral infection resulting in apoptosis prevention. The formation of a cytosolic CRT/gC1qR complex prevents cell death by reducing gC1qR translocation into the mitochondria, and we provide evidence that this mechanism is conserved from arthropods to human cancer cells. Furthermore, we show that it is possible to prevent this complex from being formed in cancer cells. When the peptides of the complex proteins are overexpressed in these cells, the cells undergo apoptosis. This finding shows a causal link between virus and cancer and may be used to develop new tools in anticancer or antiviral therapy.