Ectopic dissemination of endometrial cells and their subsequent implantation are the mechanisms involved in the development of endometriosis. While the process of dissemination appears to be a phenomenon common to all women, it is unknown what facilitates or prevents ectopic implantation of misplaced endometrial cells. Prior studies by our group and others suggest that cell-mediated immunity in patients with endometriosis is decreased. The present studies evaluated (i) peripheral blood monocyte (PBM) and peritoneal macrophage (PM) mediated cytolysis of autologous eutopic and ectopic endometrial cells and (ii) programmed cell death (apoptosis) in the eutopic and ectopic endometrium. PBM-mediated cytolysis was (mean+/-SD) 23.1+/-13% for the eutopic and 7.8+/-% for the ectopic endometrium (P < 0.004), while the corresponding percentages for PM-mediated cytolysis were 5.4+/-7 and 0.3+/-1 respectively (P < 0.04). This indicates that PBM are much more effective than PM in inducing cytolysis of both eutopic and ectopic endometrium and that ectopic endometrial cells are significantly more resistant to both PBM- and PM-mediated cytolysis. The apoptosis was significantly decreased in the eutopic endometrium of women with endometriosis as compared to fertile controls (0.375+/-0.17 versus 1.57+/-0.3, P < 0.0001). Furthermore, in matched samples apoptosis was significantly lower in the ectopic (0.149+/-0.075) than eutopic (0.375+/-0.17) endometrium (P < 0.001). We conclude from these studies that the decrease in the capacity of monocytes to mediate cytolysis of the misplaced endometrial cells in the peritoneal locations and an increased resistance of these cells to apoptosis are fundamental to the aetiology and/or pathophysiology of endometriosis.