Surgical stress and anesthesia result in systemic immunosuppression. Propofol, a commonly used anesthetic agent, alters immune cell functions. Previously we demonstrated that extracellular pressure increases macrophage phagocytosis. We hypothesized that propofol might influence pressure-induced macrophage phagocytosis in monocytes from patients undergoing surgery. Pressure (20mmHg above ambient) augmented phagocytosis by monocytes from patients -anesthetized without propofol, but reduced phagocytosis in monocytes from propofol-anesthetized patients. In vitro, propofol stimulated phagocytosis but reversed phagocytosis by pressure in THP-1 macrophages and monocytes from healthy volunteers. GABA-A receptor antagonists picrotoxin and SR 95531 did not affect basal THP-1 phagocytosis or prevent pressure-stimulated phagocytosis. However, picrotoxin and SR95531 negated the inhibitory effect of pressure in propofol-treated cells without altering propofol-induced phagocytosis. Phosphorylation of the adaptor protein p130Cas was inversely related to phagocytosis, inhibited by pressure or propofol alone, but increased by pressure and propofol together compared to propofol alone. SiRNA reduction of p130cas in THP-1 macrophages increased basal phagocytosis and prevented both pressure and propofol effects. In conclusion, propofol may alter macrophage responses to pressure via the GABAA receptor and p130cas, while pressure itself also acts via p130cas but independently of GABA-A receptors. p130cas may be an important target to modulate macrophage function in anesthetized patients.