Purpose <p>Isavuconazole is effective against invasive aspergillosis (IA) and mucormycosis (IM) and may improve clinical outcomes compared to alternative antifungal treatments. However, real-world evidence regarding its clinical use and the health economic burden of inpatient treatment for IA and IM of patients with haematological malignancies remains limited.</p> Methods <p>A retrospective, matched, multicentre cohort study was conducted in six German tertiary care centres. The study included adults with haematological or oncological diseases who were diagnosed with proven, probable, or possible IA or IM. We compared clinical and health economic outcomes under first-line treatment initiated with isavuconazole (case group) vs. liposomal amphotericin B (L-AmB) and/or voriconazole (control group) between 2016 and 2021. A micro-costing approach was used to assess direct treatment costs.</p> Results <p>We included 198 patients (99 per group), most with a probable or possible classification. Median length of hospital stay was 44 days (interquartile range [IQR] 27–74) in the isavuconazole group and 39 days (IQR 26–56) in the control group (<i>p</i> = 0.285). All-cause mortality rates were 29% and 31% (<i>p</i> = 0.530), with fungal-related deaths occurring in 21% (<i>n</i> = 6) and 23% (<i>n</i> = 7, <i>p</i> = 0.862), respectively. Mean antifungal drug acquisition and overall treatment costs were significantly higher in the isavuconazole group (€22,389 vs. €12,801, <i>p</i> = 0.003; €49,042 vs. €39,369, <i>p</i> = 0.030, respectively), while mean hospitalisation costs were comparable (€28,570 vs. €31,160, <i>p</i> = 0.406).</p> Conclusion <p>Our real-world analysis confirmed that first-line treatment initiated with isavuconazole resulted in clinical outcomes equivalent to those of L-AmB and/or voriconazole in patients with IA or IM. However, treatment costs during the in-patient stay were higher with isavuconazole.</p>