The high recurrence rate of human bladder cancer can be attributed to intraepithelial expansion of tumor cells or shedding and subsequent implantation of tumor cells elsewhere in the bladder. E-Cadherin is a calcium-dependent cell-cell adhesion molecule, and loss of E-cadherin by tumor cells is associated with increased tumor aggressiveness. Here we demonstrate that E-cadherin is also an important determinant of the mechanisms which are involved in the recurrence rate of bladder cancer. In a recently developed in vitro cocultivation model, we studied the effect of E-cadherin expression on the intraepithelial expansion pattern of six different human bladder carcinoma cell lines into primary murine urothelium. Bladder carcinoma cells lacking E-cadherin infiltrate into the primary urothelium as individual cells (pagetoid pattern). In contrast, a sharp demarcation is observed between E-cadherin-positive bladder cancer cells and the primary urothelium (carcinoma in situ pattern). With the same model, we demonstrate that only E-cadherin-positive bladder carcinoma cell lines could attach to and colonize the intact primary urothelium. We hypothesize that it is the latter process that plays an important role in the high recurrence rate that is observed in some of the patients.