Triggering receptor expressed on myeloid (TREM)‐1 is integral to the inflammatory response occurring during septic shock, although its precise function has yet to be determined. Here we show that in vivo silencing of TREM‐1 using siRNA duplexes in a fecal peritonitis mouse model resulted in a blunted inflammatory response and increased mortality. This was associated with impaired bacterial clearance related to marked inhibition of the neutrophil oxidative burst. By contrast, TREM‐1‐silenced mice were highly resistant to a lethal endotoxin challenge, while partial silencing of TREM‐1 in the bacterial peritonitis model produced a significant survival benefit. These data highlight the crucial role of the TREM‐1 pathway in mounting an adequate inflammatory and cytotoxic response to polymicrobial sepsis, and both the therapeutic promise and potential risks of its modulation.