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Abstract Background Isavuconazole (ISA) is a newer triazole which has activity against most mold species and has been utilized for prophylaxis as well as treatment in patients with hematologic malignancies (HM) and hematopoietic stem cell transplant (HSCT). However, several studies have documented breakthrough invasive fungal infections (bIFIs). Thus, we conducted a systematic review and meta-analysis to investigate the incidence of bIFIs among patients receiving ISA prophylaxis. Methods We conducted a systematic review and meta-analysis of the published literature using the concept of ISA, HSCT and HM from 5 search engines. Pooled incidence of bIFI while on ISA prophylaxis in patients with HSCT and HM, was calculated using DerSimonian-Laird random effect model. Results Thirty-five and 19 studies were included in the systematic review, and the meta-analysis, respectively. Total of 991 patients were identified as using ISA prophylaxis, and the majority had either acute myeloid leukemia or myelodysplastic syndrome (69.9%). The pooled incidence of proven/probable bIFIs was 7% (95% CI 4-12%, I2: 55%). The most common pathogen was Aspergillus species (43.1%), followed by Candida (22.4%), and Mucorales (12.1%). In 19 studies, mortality was documented and ranged between 0-100%, majority of which were more than 50%. Conclusions We found high incidence of bIFIs while on ISA prophylaxis in HM/HSCT recipients, with high mortality. Given the lack of randomized clinical trials evaluating ISA in this indication, it’s role in prophylaxis remains unclear.