Aims Cytochrome 2C19 genotype‐directed dosing of voriconazole (VRC) reduces the incidence of insufficient VRC trough concentrations ( C min ) but does not account for CYP3A polymorphisms, also involved in VRC metabolism. This prospective observational study aimed to evaluate the utility of a genetic score combining CYP2C19 and CYP3A genotypes to predict insufficient initial VRC C min (<1 mg/L). Methods The genetic score was determined in hematological patients treated with VRC. The higher the genetic score, the faster the metabolism of the patient. The impact of the genetic score was evaluated considering initial VRC C min and all VRC C min (n = 159) determined during longitudinal therapeutic drug monitoring. Results Forty‐three patients were included, of whom 41 received VRC for curative indication. Thirty‐six patients had a genetic score ≥2, of whom 11 had an initial insufficient VRC C min . A genetic score ≥2 had a positive predictive value of 0.31 for having an initial insufficient VRC C min and initial VRC C min was not associated with the genetic score. The lack of association between the genetic score and VRC C min may be related to the inflammatory status of the patients (C‐reactive protein [CRP] levels: median [Q1‐Q3]: 43.0 [11.0‐110.0] mg/L), as multivariate analysis performed on all VRC C min identified CRP as an independent determinant of the VRC C min adjusted for dose ( P < .0001). Conclusion The combined genetic score did not predict low VRC exposure in patients with inflammation, which is frequent in patients with invasive fungal infections. Strategies for the individualization of VRC dose should integrate the inflammatory status of patients in addition to pharmacogenetic variants.