Vitamin D modulates immune response， induces endogenous antimicrobial peptide production， and enhances innate immunity to defend against infections. These findings suggest that incorporating vitamin D into medical devices or scaffolds could positively modulate host immune response and prevent infections. In the current study， we evaluated host responses and endogenous antimicrobial peptide production using 25-hydroxyvitamin D (25(OH)D)-eluting radially aligned PCL nanofiber scaffolds in human immune system-engrafted mice. We transformed traditional 2D electrospun nanofiber membranes into radially aligned PCL nanofiber scaffolds using the concept of solid of revolution and an innovative gas-foaming technique. Such scaffolds can promote rapid cellular infiltration and neovascularization. The infiltrating immune cells within subcutaneously implanted 25(OH)D-containing scaffolds mainly consisted of human macrophages in the M1 phase (CCR7)， mice macrophages in the M2 phase (CD206)， and human cytotoxic T cells (CD8) other than few human T-helper cells (CD4). The 25(OH)D-eluting nanofiber scaffolds significantly inhibited the production of pro-inflammatory cytokines (TNF-α， IL-6)， while accelerating the production of anti-inflammatory cytokines (IL-4， IL-10) within the scaffolds. Additionally， we observed increased expression of human cathelicidin LL-37 within the 25(OH)D-eluting scaffolds， while no LL-37 expression was observed in the control. Together， these findings support further work in the design of vitamin D-eluting medical devices or scaffolds for modulating immune response and promoting antimicrobial peptide production. This could potentially reduce the inflammatory response， prevent infections， and eventually improve success rates of implants. STATEMENT OF SIGNIFICANCE: Transplant failure of medical devices， grafts， scaffolds， and tissue-engineered constructs due to inflammation and infection causes not only economic losses but also sufferings of second operation to the patient. Positive modulation of the host response to implants， scaffolds， and tissue-engineered constructs is likely to reduce the failure rate. Vitamin D plays an important role in modulating the immune response. It is able to not only reduce inflammation and induce endogenous antimicrobial peptide production but also prevent multidrug resistance and other side effects of traditional antibiotics. In this study， host responses to 25-hydroxyvitamin D (25(OH)D)-eluting radially aligned PCL nanofiber scaffolds were evaluated in human immune system-engrafted mice. The 25(OH)D-eluting medical devices or scaffolds were able to modulate positive immune response and promote antimicrobial peptide production. This work presented an innate immunity-enhancing approach for reducing the inflammatory response and preventing infections， likely resulting in improvement of success rates of implants.