OBJECTIVE: To provide new details on the pseudomyxoma peritonei (PMP) microenvironment and discuss its potential role on the clinical behavior of this tumor. STUDY DESIGN: In the present study, in addition to routine histology, immunostains for CD68, CD3, CD20, Ki-67, CD34, LYVE-1, and the tumor-associated antigens (TAAs) pituitary-tumor transforming gene 1 (PTTG1) and squamous cell carcinoma antigen 1 (SCCA1) were explored. Fourteen consecutive patients who underwent cytoreductive surgery with hyperthermic intraoperative peritoneal chemotherapy were included in the study. RESULTS: We found the presence of variable amounts and pattern distributions of CD68+ cells, CD3+ T-cells, and CD20+ B-cells in the PMP microenvironment. CD3+ lymphocytes were grouped in clusters in 7 out of 14 (50%) PMPs, while only 4 out of 14 (29%) had dispersed CD20+ lymphocytes. CD68+ macrophages were always found dispersed throughout the PMP microenvironment. PMPs have been also found highly vascularized by blood vessels when compared to LYVE-1+ lymphatic vessels, and variably proliferative as shown by different Ki- 67+ cell densities. Additionally, PMPs were immunopositive for PTTG1 and SCCA1, 2 TAAs previously associated with the progression and recurrence of various human malignancies. CONCLUSION: Our findings highlight unknown features about PMP microenvironment organization and represent a basis for additional studies including a large cohort of patients to reveal helpful information on the clinical behavior of this tumor. © Science Printers and Publishers, Inc.