Microglia are important in the inflammatory response in Alzheimer’s disease (AD). We previously showed that macrophage colony stimulating factor receptor (M-CSFR), encoded by the c-fms protooncogene, is overexpressed on microglia surrounding amyloid beta (Abeta) deposits in APPV717F mouse model for AD. The M-CSFR is also increased on microglia after experimental brain injury and in AD. To determine the relevance of these findings we transiently expressed M-CSFR on murine BV-2 and human SV-A3 microglial cell lines using a SV-40 promoted c-fms construct. M-CSFR overexpression resulted in microglial proliferation and increased expression of iNOS, the proinflammatory cytokines interleukin-1-alpha, macrophage inflammatory protein 1-alpha, interleukin-6 and of macrophage colony stimulating factor (M-CSF) itself. Antibody neutralization of M-CSF showed that the M-CSFR-induced proinflammatory response was dependent on M-CSF in the culture media. Using a co-culture of c-fms transfected murine microglia and rat organotypic hippocampal slices and a species-specific real-time RT-PCR assay and ELISA, we showed that M-CSFR overexpression on exogenous microglia induced expression of IL-1-alpha by the organotypic culture. These results show that increased M-CSFR expression induces microglial proliferation, cytokine expression and a paracrine inflammatory response, suggesting that in APPV717F mice, increased M-CSFR on microglia could be an important factor in Abeta-induced inflammatory response.