Abstract: (2022) 23:472 Askari et al. Trials https://doi.org/10.1186/s13063-022-06375-w Open Access RESEARCH The efficacy of curcumin‑piperine co‑supplementation on clinical symptoms, duration, severity, and inflammatory factors in COVID‑19 outpatients: a randomized double‑blind, placebo‑controlled trial Gholamreza Askari1,2,3, Amirhossein Sahebkar4,5,6, Davood Soleimani7, Atena Mahdavi3, Sahar Rafiee3, Muhammed Majeed8, Farzin Khorvash9, Bijan Iraj10, Mahshid Elyasi3, Mohammad Hossein Rouhani1 and Mohammad Bagherniya1,2,3*    Abstract Background: COVID-19 pandemic has made the disease a major global problem by creating a significant burden on health, economic, and social status. To date, there are no effective and approved medications for this disease. Curcumin as an anti-inflammatory agent can have a positive effect on the control of COVID-19 complications. This study aimed to assess the efficacy of curcumin-piperine supplementation on clinical symptoms, duration, severity, and inflammatory factors in patients with COVID-19. Methods: Forty-six outpatients with COVID-19 disease were randomly allocated to receive two capsules of curcumin-piperine; each capsule contained 500 mg curcumin plus 5 mg piperine or placebo for 14 days. Results: Mean changes in complete blood count, liver enzymes, blood glucose levels, lipid parameters, kidney function, and c-reactive protein (CRP) were not significantly different between the two groups. There was a significant improvement in health status, including dry cough, sputum cough, ague, sore throat, weakness, muscular pain, headache, and dyspnea at week 2 in both curcumin-piperine and placebo groups (P value < 0.05); however, the improvement in weakness was more in the curcumin-piperine group than with placebo group (P value 025). Conclusion: The present study results showed that curcumin-piperine co-supplementation in outpatients with COVID-19 could significantly reduce weakness. However, in this study, curcumin-piperine co-supplementation could not significantly affect the other indices, including biochemical and clinical indices. Trial registration: Iranian Registry of Clinical Trials IRCT2​01212​16011​763N46. 2020-10-31 Keywords: COVID-19, Curcumin, Piperine, Clinical trial, Clinical symptoms *Correspondence: baghrerniya@nutr.mui.ac.ir 1 Food Security Research Center, Isfahan University of Medical Sciences, PO Box: 00983137922110, Isfahan, Iran Full list of author information is available at the end of the article