Muscle fatigue and cognitive disturbances persist in patients after recovery from acuteCOVID-19 disease. However, there are no specific treatments for post-COVID fatigue. Objective: Toevaluate the efficacy and safety of the health supplements ImmunoSEB (systemic enzyme complex)and ProbioSEB CSC3 (probiotic complex) in patients suffering from COVID-19 induced fatigue.A randomized, multicentric, double blind, placebo-controlled trial was conducted in 200 patientswith a complaint of post-COVID fatigue. The test arm (n= 100) received the oral supplements for14 days and the control arm (n= 100) received a placebo. Treatment efficacy was compared usingthe Chalder Fatigue scale (CFQ-11), at various time points from days 1 to 14. The supplementaltreatment resulted in resolution of fatigue in a greater percentage of subjects in the test vs. the controlarm (91% vs. 15%) on day 14. Subjects in the test arm showed a significantly greater reductionin total as well as physical and mental fatigue scores at all time points vs. the control arm. Thesupplements were well tolerated with no adverse events reported. This study demonstrates that a14 days supplementation of ImmunoSEB + ProbioSEB CSC3 resolves post-COVID-19 fatigue and canimprove patients’ functional status and quality of life.