Objective <p>Voriconazole is a commonly used antifungal medication, particularly for treating invasive pulmonary aspergillosis and as prophylaxis in hematologic malignancies. However, it can cause adverse effects, including periostitis—a painful inflammation of the periosteum. Reported incidence rates of voriconazole-induced periostitis vary widely. This study aimed to determine the incidence and characteristics of voriconazole-induced periostitis in a large cohort of patients with hematologic malignancies at a tertiary medical center, using various imaging modalities.</p> Methods <p>A retrospective cohort study was conducted at Rambam Health Care Campus, including patients treated with voriconazole for at least 90 days between September 2015 and December 2022. Patients diagnosed with invasive pulmonary aspergillosis were evaluated. Imaging studies performed post-treatment initiation were reviewed for periostitis, confirmed by senior radiologists.</p> Results <p>Among 157 patients treated for invasive pulmonary aspergillosis, 110 met the inclusion criteria. Four patients (3.6%, 95% CI 1.0% − 8.8%) demonstrated radiological signs of periostitis, most commonly detected via chest CT. Humeral involvement was present in all cases, and rib involvement occurred in 75%. Follow-up imaging did not show resolution due to ongoing treatment, patient mortality, or lack of follow-up.</p> Conclusion <p>The incidence of voriconazole-induced periostitis in this cohort was lower than previously reported. Although rare, periostitis can significantly impact patient comfort and treatment decisions.</p> Clinical trial <p>Not applicable</p>