Monocytes play a critical role as both phagocytes and mediators of inflammatory responses in the prevention of cardiovascular device‐related infections. However, persistent infection of these devices still occurs and may be attributed to deleterious cellular alterations resulting from monocyte interactions with a foreign material in an environment of dynamic flow. Thus, the effects of both shear stress and adhesion to material surfaces on human monocyte apoptosis were investigated. A rotating disk system generated physiologically relevant shear stress levels (0–14 dyn/cm²), and shear‐related apoptosis occurring in adherent monocytes was characterized. Using annexin V analysis, apoptosis of polyurethane‐adherent monocytes under shear for 4 h increased to levels >70% with increasing shear in a near‐linear fashion (r² = 0.713). It was qualitatively confirmed using confocal microscopy that filamentous (F)‐actin distribution was altered, that DNA fragmentation occurred, and that activated caspases were involved in shear‐induced apoptosis. Static studies determined that spontaneous apoptosis was material‐dependent over 72 h by demonstrating marked differences between apoptosis of monocytes adherent to a polyurethane compared to an alkyl‐modified glass. Treatment with TNF‐α augmented this material dependency in a dose‐dependent fashion over time. F‐actin content of TNF‐α‐treated cells decreased to <62% of untreated cells. We conclude that concomitant effects from both material surfaces and dynamic flow mediate human monocyte apoptosis and may have serious implications in the context of implanted cardiovascular device infection. © 2002 Wiley Periodicals, Inc. J Biomed Mater Res 60: 148–158, 2002