It has recently been shown that an increased plasma level of the tryptophan catabolite kynurenine is an early indicator for the development of sepsis in major trauma patients. We examined the predictive value of kynurenine pathway activity for ongoing sepsis in patients being admitted to a surgical intensive care unit for different reasons. In addition, we asked whether an accumulation of kynurenines in patients’ plasma depends on reduced renal clearance. We conducted a prospective observational study including 100 consecutive patients and monitored laboratory variables, physiological and adverse events, sepsis and outcome. Using tandem mass spectrometry, we quantified the five indoleamines tryptophan, serotonin (5-HT), kynurenine, quinolinic acid and kynurenic acid at baseline and twice a week during the intensive care unit stay. Among the patients enrolled, 50 did not develop sepsis in the intensive care unit (non-septic), 18 patients did not have sepsis at baseline but developed sepsis later on (preseptic) and 32 patients already fulfilled the criteria of severe sepsis and septic shock at baseline (septic). In general, non-septic critically ill patients showed activation of the kynurenine pathway, but septic shock coincided with an exacerbation of kynurenine pathway activity even in the absence of renal failure. Importantly, plasma concentrations of quinolinic acid (area under the curve 0.832 [95% confidence interval 0.710 to 0.954]) and the Quin/Trp ratio (area under the curve 0.835 [95% confidence interval; 0.719 to 0.952]) showed the best discrimination between non-septic and pre-septic patients at baseline. These findings open new avenues for further investigations on the pathophysiology of sepsis.