Objectives: To evaluate the complement related pattern recognition molecules (PRMs) PTX3, MBL, CL-11, ficolin-2 and -3, along with the established marker CRP, to predict 28-day mortality and disease severity of sepsis in patients admitted to the intensive care unit (ICU). Methods: In a single-center, prospective, observational study 547 patients were included over a period of 18 months. Blood samples were obtained at admission to the ICU and the following 4 days. Results: PTX3 baseline levels were significantly higher in non-survivors compared to survivors, whereas MBL and ficolin-2 levels were significantly lower in non-survivors compared to survivors. A PTX3 level above the median was independently associated with 28-day mortality in the adjusted analysis including age, sex, chronic disease and immunosuppression (HR 1.87, 95% CI [1.41–2.48], p < 0.0001), while a MBL level above the median was associated with increased chance of survival (HR 0.75, 95% CI [0.57–0.98], p = 0.034). Ficolin-2 was only borderline significant (HR 0.79, 95% CI [0.60–1.03], p = 0.084). In a ROC analysis PTX3 was superior to CRP in predicting septic shock. Conclusions: PTX3, MBL and CRP levels were independently associated with 28-day mortality in ICU patients. PTX3 was a better marker of septic shock compared to CRP.