BACKGROUND: Studies have proposed a link between psoriasis and imbalanced gut microbiome. Therefore, the modulation of the gut microbiota with probiotics may improve clinical outcomes, chronic inflammation, and cardiovascular risk factors in patients with psoriasis. METHODS: In a randomized double-blind placebo-controlled clinical trial, forty-six patients with psoriasis randomly assigned into probiotic capsules contains multi-strain at least 1.6× 109 CFU/g bacteria or placebo for two months. Psoriasis Area and Severity Index (PASI), blood pressure, quality of life (QOL) pro-inflammatory cytokines (hs-CRP and IL1-β), and lipopolysaccharides (LPS) were measured. RESULTS: Improvements in QOL was significant in patients taking probiotics supplementation comparing to the placebo group and PASI (-5.06±2.10 vs 0.30±1.80, P=0.049) as well. After the intervention, a considerable reduction in serum LPS levels (-7.21±10.33 vs -2.74±0.97 mmol/L, P=0.010), hs-CRP levels (-1.67±0.95 vs -0.70+ 0.38 mg/L, P=0.013), and IL1- β levels (-1.64±1.10 vs 0.17+ -0.20 mg/L, P=0.043) in the probiotics group. CONCLUSION: This study shows that probiotics significantly improved the quality of life and seriousness in psoriatic patients. Moreover, it enhances cardiovascular risk factors and inflammatory/oxidative stress markers. TRIAL REGISTRATION: This trial also was recorded in the Iranian registry of clinical trials (https://www.irct.ir) (code: IRCT20191124045483N1). J Drugs Dermatol. 2022;21(6):637-644. doi:10.36849/JDD.6237.