Introduction: Sepsis remains a major clinical challenge due to its frequent complications and high mortality rates. Biomarkers with an ability to early identify septic patients with a higher risk of mortality and complications are crucial for timely interventions and therapy management. The endocannabinoid system is recognized as a key regulator of immune function during inflammation. The two main endocannabinoids are arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG). Study design and aim: The study was designed as a prospective cohort study with the aim of assessing the prognostic value of anandamide and 2-AG in early sepsis mortality and complication prediction. Subjects and methods: Sepsis complications were defined as septic shock (SS), and a need for invasive mechanical ventilation (IMV) and vasoactive therapy (VT). A total of 106 patients with sepsis aged >18 years were included in this study. Septic patients were divided into groups based on observed outcomes: survivors (N=53) and non-survivors (N=53), SS (N=25) and non-SS (N=81) group, IMV (N=26) and non-IMV (N=80) group, VT (N=28) and non-VT (N=78) group. Blood samples were collected at the time of admission to the emergency department. Additional blood samples were collected at the end of hospitalization from patients with the survival outcome. Results: Early on admission, lower concentrations of anandamide and 2-AG were observed in the SS, IMV, and VT groups of patients with sepsis. Anandamide was found to be an independent risk factor for IMV and VT requirement with better or comparable performance to the inflammatory biomarkers C-reactive protein, procalcitonin, and interleukin-6. Although anandamide was recognised as a prognostic marker of sepsis mortality, markers and scores of organ damage in sepsis play a more important role in mortality prediction. At the end of hospitalization, endocannabinoids showed no change in plasma concentrations, indicating their possible important role in tissue regeneration. The correlation of the two endocannabinoids was high in all four observed outcomes, except for the SS, IMV, and VT groups, indicating different roles of anandamide and 2-AG in unwanted sepsis outcomes. Conclusion: Early at hospital admission, baseline anandamide and 2-AG concentrations predicted SS development, as well as IMV and VT requirements in septic patients. These findings support the role of endocannabinoids as important regulators of inflammation and sepsis in humans.