Cell-cell contact is thought to be critically involved in mechanisms leading to radioresistance. Here, we assessed the influence of confluent compared to subconfluent cell culture conditions and the radiosensitizing ability of E-cadherin inhibition alone or in combination with C225-mediated EGFR inhibition in human squamous cell carcinoma cells. Our results show higher radioresistance under subconfluent growth conditions than under confluency. Delayed plating only resulted in higher radiation survival in confluently growing cells. While E-cadherin depletion significantly reduced basal clonogenic survival, increased the rate of apoptosis, and diminished cell adhesion, the cellular radiosensitivity remained unchanged under both subconfluent and confluent conditions. C225 decreased basal cell survival but failed to modify radiation survival. Additional treatment of E-cadherin knockdown cell cultures with C225 did not further reduce basal cell survival or lead to radiosensitization. Interestingly, E-cadherin silencing in 3D cell cultures did not alter radiosensitivity. Our data indicate that cell-cell contact and E-cadherin are not prominently involved in the regulation of radioresistance of human squamous cell carcinoma cells. In addition, no regulatory interaction between E-cadherin and EGFR in the radiation response was observed.