Prostate cancer (PCa) is the most common cancer in men in Western countries. In China, the incidence has sharply increased for the past 20 years. Prostate cancer preferentially metastasizes to bone resulting in high mortality. We have previously reported that the presence of CC chemokine ligand 2 (CCL2) produced by prostate cancer (PCa) epithelial cells, stroma/osteoblasts, and bone marrow endothelial cells, is pro-tumorigenic for prostate cancer cells. CCL2 increases prostate cancer cell proliferation, migration, and survival and induces osteoclast formation. Moreover, the key role of CCL2 in the tumor growth and metastasis has been linked to its regulatory role in mediating monocyte/macrophage infiltration into the tumor microenvironment. Using a model of human PCa cells implanted in mice, Loberg R. et al. reported that anti-murine CCL2 neutralizing antibodies resulted in greater reduction of overall tumor burden compared to the use of anti-human antibody (anti-tumor cell-derived). This suggests that host-derived CCL2 may play a key role in prostate tumor growth and metastasis. Therefore, in this study, we have employed CCL2 knockouts which were interbred to SCID mice to generate colonies of homozygous SCID/CCL2-/- mice. PCa cells (PC3Luc) were injected into the left ventricle (Intracardiac-injection) of SCID/CCL2-/- and wild-type controls (n=20/group). The effects of deletion of CCL2 in the host on prostate cancer cell homing, growth in bone and bone destruction were evaluated for 4 weeks. In a parallel experiment, PC3Luc cells were subcutaneously implanted and tumor size was monitored weekly for 4 weeks. This parallel study addressed bone-specific vs. generalized influences of host-derived CCL2 on prostate cancer growth. We found that skeletal metastases occurred in 4/20 SCID/CCL2-/- mice vs 14/20 WT mice. In addition, X-ray photographs showed significantly fewer bone resorptive lesions in SCID/CCL2-/- mice vs. WT mice. Histology examinations confirmed x-ray findings. In the parallel experiment, PC3Luc tumor grew slower in SCID/CCL2-/- mice vs. WT mice. These results indicate that host-derived CCL2 production defines a permissive microenvironment for prostate cancer growth and skeletal metastasis. These findings may significantly impact the therapeutic field through targeting “the host” instead of “the tumor cells” in prostate cancer. Supported by U.S. Department of Defense PC061231 (J. Zhang), National Natural Sciences Foundation Key Project (81130046, J. Zhang) and National Natural Science Foundation Project (81171993, Y. Lu).