Anti-tumor activity of mTOR-inhibitor rapamycin has been shown in various tumors. Based on observations on a transplanted patient, recieving rapamycin, we wanted to evaluate the potential of rapamycin for the treatment of colorectal peritoneal carcinomatosis alone or in combination with surgery. We established syngenic, orthotopic animal models with CT26 peritoneal tumors in Balb/C mice and orthotopic xenograft models with SW620 in nude mice. Rapamycin was administered intraperitoneally or per gavage, alone or combined with 5-FU and oxaliplatin. Tumor growth was analyzed and expression of tissue inhibitor of matrix-metalloproteinases 1 (TIMP-1) in the tumor and serum was determined by ELISA.Rapamycin downregulated TIMP-1 in-vitro. In-vivo, rapamycin markedly suppressed growth of established syngenic and xenografted peritoneal tumors (P<0.01). This anti-tumor effect was comparable after intraperitoneal or oral administration. Tumor suppression was further increased when rapamycin was combined with 5-FU and/or oxaliplatin. TIMP-1 serum levels correlated well (Correlation Coefficient = 0.75; P<0.01) with rapamycin activity.Hence, rapamycin suppressed advanced stage colorectal cancer growth even when applied orally. The combination of rapamycin with current chemotherapy regimens significantly increased anti-tumor efficacy without apparent toxicity. Because the treatment effect can be monitored by serum TIMP-1, clinical trials should now be considered.