Background/Objectives: Men are more susceptible to sepsis than women, but the underlying pathways have not been fully clarified. Lipopolysaccharide-binding protein (LBP) is an acute-phase protein that is highly elevated in sepsis. Experimental evidence shows that LBP increases to a much greater extent in male than in female mice following exposure to lipopolysaccharide. However, gender-specific studies of circulating LBP levels in sepsis patients are scarce. Methods: In the plasma of 189 patients with systemic inflammatory response syndrome (SIRS), sepsis, and septic shock, LBP levels were measured by enzyme-linked immunosorbent assay. Results: Patients with liver cirrhosis had reduced circulating LBP levels, regardless of gender. Further analysis within the non-cirrhotic patients showed no significant differences in LBP levels between sexes in patients with SIRS, sepsis, and septic shock. Ventilation, dialysis, and vasopressor therapy had no effect on LBP levels in either sex. A positive correlation between LBP and C-reactive protein was observed in the total cohort, males, and females. Infection with Gram-negative or Gram-positive bacteria had no effect on plasma LBP levels in males. However, female patients with Gram-negative infection had increased plasma LBP levels compared to females with negative and Gram-positive blood cultures, and 70 µg/mL LBP discriminates Gram-negative infections in females with a sensitivity of 88% and a specificity of 74%. Infection with SARS-CoV-2 did not change plasma LBP levels in either men or women. Female patients who did not survive had lower plasma LBP levels compared to female survivors and male non-survivors. Conclusions: This investigation highlights the influence of sex on plasma LBP levels in SIRS/sepsis patients, suggesting that LBP could be a sex-specific biomarker in critically ill patients.