Innate host defense critically depends on efficient phagocytosis which is mainly mediated by polymorphonuclear neutrophils (PMN). Phagocytosis is facilitated upon opsonization of bacteria by the complement factor iC3b which is recognized by the integrin CD11b/CD18. Here, we studied the functional impact of the non-receptor tyrosine kinase Syk for efficient CD11b/CD18-mediated phagocytosis of iC3b-opsonized E. coli. By means of confocal microscopy, we found that CD18 colocalized with Syk during phagocytosis of iC3b-opsonized E. coli. Syk was associated with its downstream target Vav, a guanine nucleotide exchange factor for the small GTPases Rac and Cdc42. The Syk specific inhibitor piceatannol (30 mM) abolished the colocalization of Syk and Vav with the iC3b-opsonized bacteria. Inhibition of Syk by piceatannol (30 mM) or downregulation of Syk by RNAi technique significantly inhibited phagocytosis of iC3b-opsonized E. coli within 10 min to 41.6%± 2.5% and 24.8%± 18.7 (p < 0.005) when compared to phagocytosis of untreated control cells (100%). Similar results were obtained using murine Syk deficient PMN. In conclusion, our data indicate that Syk is required for efficient CD11b/CD18-mediated phagocytosis of iC3b-opsonized bacteria. Supported by DFG (WA 1048/2-1).