https://www.medrxiv.org/content/10.1101/2021.07.14.21259081v1 Background Coronavirus disease 2019 (COVID-19) is a serious respiratory disease that results from infection with a newly discovered coronavirus (SARS-COV-2). Unfortunately, COVID-19 is not only a short-term infection but that patients (pts) recovering from SARS-CoV2 infection complain of persisting symptoms including: fatigue, diffuse myalgia and weakness, which may lead to chronic fatigue syndrome. There is currently no evidence that nutritional supplements and/or physical exercise can assist in the recovery of pts with chronic fatigue syndrome. 1-Methylnicotinamide (1-MNA) is an endogenic substance that is produced in the liver when nicotinic acid is metabolized. 1-MNA demonstrates anti-inflammatory and anti-thrombotic properties. Therefore, we investigated whether 1-MNA supplements could improve exercise tolerance and decrease fatigue among patients recovering from SARS-CoV-2. Methods The study population was composed of pts after COVID-19, expressing subjective feelings of limited tolerance to exercise. The selected pts were randomized into two groups: GrM0 – without supplementation; GrM1 – with 1-MNA supplementation. At the beginning of the study (Phase 0), in both groups, a 6-minute walk test (6MWT) was carried out and fatigue assessment with Fatigue Severity Scale (FSS) was performed. After 1 month (Phase 1), a follow up FSS and 6MWT once more were performed in both groups. Results A significant improvement in the mean distance covered in the 6MWT was noted among the pts in GrM1, compared to those in GrM0. We also noted that in GrM1 the 6MWT distance was significantly higher after 1 month of supplementation with 1-MNA, compared to the beginning of the study (515.18 m in Phase 0 vs 557.8m in Phase 1; p = 0.000034). In GrM1, significantly more pts improved their distance in the 6MWT (23 out of 25 pts, equal to 92%), by a mean of 47 meters, compared to GrM0 (15 of 25 pts, equal to 60%) (p = 0.0061). After one month, significantly more patients in the group without 1-MNA had severe fatigue (FSS ≥ 4) compared to the group with supplementation (GrM1 = 5 pts (20%) vs GrM0 = 14pts (56%); p = 0.008). Conclusions 1-MNA supplementation significantly improved physical performance in a 6-minute walk test and reduced the percentage of patients with severe fatigue after COVID-19. The comprehensive action of 1-MNA, including anti-inflammatory and anticoagulant effects, as well as activation of the SIRT1 enzyme, may be beneficial for the recovery of patients with persistent symptoms of fatigue and low tolerance to exercise after COVID-19.