Background <p>Dendritic cells (DCs) regulate the balance between immune activation and tolerance. Given the immunomodulatory properties of voriconazole, this study investigated its effects on the maturation, activation, and inflammatory profile of human monocyte-derived DCs.</p> Methods and Results <p>PBMCs were isolated from healthy human blood donors using Ficoll density gradient centrifugation. Monocytes were isolated via plastic adherence and then differentiated into monocyte-derived dendritic cells (moDCs). The cells were treated with voriconazole and LPS, or with LPS alone. The expression levels of CD11c, CD14, HLA-DR, and CD86 on dendritic cells (DCs) were evaluated by flow cytometry. The mRNA levels of genes and cytokines involved in DC maturation and function were quantified by qRT-PCR and ELISA. The research demonstrated that voriconazole-treated dendritic cells expressed higher levels of CD11c (<i>p</i> ≤ 0.001), HLA-DR (<i>p</i> ≤ 0.0001), and CD86 (<i>p</i> ≤ 0.0001), which are markers of maturation and antigen presentation, respectively. Voriconazole suppressed the expression of both anti-inflammatory and inflammatory genes, such as IL-10 (<i>p</i> ≤ 0.0001), IDO (<i>p</i> ≤ 0.0001), IL-18 (<i>p</i> ≤ 0.0001), and TNF-α (<i>p</i> ≤ 0.0001), in dendritic cells. Significant decreases in the concentrations of IL-1β (<i>p</i> ≤ 0.0001) and TNF-α (<i>p</i> ≤ 0.001) cytokines were observed according to ELISA data, although IL-12 levels did not change appreciably (not significant).</p> Conclusion <p>Voriconazole increased the expression of dendritic cell maturation markers, enhancing the maturation process and readiness for antigen presentation. In addition, voriconazole reduced the expression of inflammatory and anti-inflammatory genes. The corresponding decrease in protein levels further indicated balanced immune regulation. These findings highlight the immunomodulatory potential of voriconazole and warrant further investigation.</p> Graphical abstract <p></p>