Genetic factors may predispose critically ill patients to increased risk of developing sepsis. Mannose-binding lectin (MBL) is an important factor in innate immune defense. We investigated whether MBL gene polymorphisms causing low levels of MBL are associated with the development and progression of sepsis in adult patients in intensive care units. In 272 prospectively monitored patients with systemic inflammatory response syndrome, different MBL genotypes were compared, with respect to microbiology, sepsis development, and survival. The presence of MBL variant alleles was associated with the development of sepsis, severe sepsis, and septic shock. An increased risk of fatal outcome was observed in patients carrying variant alleles. These data show that MBL insufficiency plays an important role in the susceptibility of critically ill patients to the development and progression of sepsis and confers a substantial risk of fatal outcome.