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MARVELD1 is integral to the inflammatory response occurring during septic shock, although its precise function has yet to be determined. Here we show that compared with wildtype mice, listeria monocytogenes (LM)-induced septic shock in MARVELD1 knockout mice resulted in a heightened pro-inflammatory response and increased mortality. This observation was associated with impaired bacterial clearance related to marked inhibition of the macrophage phagocytic acitivity in MARVELD1 knockout mice. Consistently, the MARVELD1 knockout mice were more sensitive to a lethal endotoxin or LM challenge, while wildtype mice in the bacterial peritonitis model produced a significant survival benefit. These data highlight the crucial role of the MARVELD1 pathway in inducing an adequate macrophage response to polymicrobial sepsis, and both the therapeutic promise and potential risks of its modulation.