Previous studies indicate a novel role for the osteoclast-associated receptor (OSCAR) in oxidative stress-mediated atherogenesis. However, the functional role of OSCAR in endothelial cells is unknown. Here we characterized OSCAR signaling in human endothelial cells using a proteomic approach. OSCAR was either overexpressed or silenced, and the functional effects were assessed by an in-depth proteomic study using stable isotope labeling with amino acids in cell culture (SILAC). Reduction of complexity using subcellular protein fractions from the membrane, the cytosol, and the nucleus of human endothelial cells enabled the detection of 4975 unique proteins. Of these proteins, OSCAR overexpression regulated 145 and OSCAR silencing regulated 110. These proteins were mainly involved in cellular proliferation, inflammatory response and cell-to-cell signaling. Interestingly, OSCAR modulation reciprocally regulated signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3). Thus, STAT1 and several interferon-induced proteins showed a clear inverse correlation to OSCAR expression, which was further verified by Western blot analysis. In contrast, it was found that OSCAR overexpression activated STAT3. Furthermore, OSCAR overexpression increased proteins involved in cell adhesion, which correlated with an increased adhesion of monocytes to the endothelium after OSCAR overexpression. In conclusion, using a comprehensive proteomic approach, endothelial cell-derived OSCAR was found to be involved in the STAT signaling pathway and to affect monocyte adhesion. This indicates a novel role of OSCAR in the vascular-immune cross-talk.