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Objectives: Vitamin D deficiency is prevalent in heart failure (HF) and the anti-inflammatory impacts of vitamin D may affect the pathogenesis of HF. Therefore, the present study aimed to investigate the effect of vitamin D supplementation on echocardiographic and biochemical factors in vitamin D-deficient HF patients. Materials and Methods: To this end, 39 HF patients with 25(OH)D ≤20 ng/mL participated in the current double-blind, randomized, and placebo-controlled trial, who belonged to class III, New York Heart Association classification. About 50000 IU vitamin D3 (group D+) or placebo (group D- ) were prescribed within 2 months. Then, the ejection fraction (EF%), tumor necrosis factor alpha (TNF-α), B-type natriuretic peptide (BNP), and high sensitive C-reactive protein (hs-CRP) were assessed before and after supplementation. Results: The mean serum level of 25(OH)D increased markedly in D+ group (P<0.001). The mean increase of EF% was 5.3±9.03% (P=0.03) and the decrease of TNF-α (-0.09 pg/mL, P<0.001) and BNP (-3.14 ng/mL, P=0.04) were statistically significant in D+ group after supplementation. In addition, the blood concentration of BNP declined significantly in D+ group compared to placebo while hs-CRP and TNF-α levels failed to differ between the two groups. Conclusions: The results revealed that vitamin D could be effective against inflammation and thus its supplementation may reduce the severity of HF by improving the serum level of BNP and EF%. However, more clinical trials are required to approve the beneficial role of vitamin D in HF patients.