Objectives: Platelet refractoriness complicates the platelet transfusion, which is essential for managing thrombocytopenia in patients with hematological disorders. It is associated with adverse clinical outcomes and increased health care costs. We conducted a prospective study to determine the effectiveness of cross-matched compatible platelets in a group of patients refractory to platelets from random donors and to evaluate human leukocyte antigen (HLA)-mediated refractoriness. Methods: This prospective study was conducted on 40 patients with different hematological disorders requiring platelet transfusions who were refractory to random platelets and presented to the hematology unit of Alexandria's main university hospitals between May 2020 and March 2021. They received 60 ABOcompatible platelet transfusions, either leuco-reduced or random donor platelets, stored for no more than 72 hours. A solid-phase red cell adherence technique (SPRCA) was used for platelet crossmatching. The corrected count increment (CCI) was used to monitor the effectiveness of each platelet transfusion with a cut-off value of 5 × 103 /µL at 1 hour and 2.5 × 103 /µL at 24 hours. Anti-HLA antibodies were assessed using the enzymelinked immunosorbent assay technique. Results: Out of 60 cross matches, 47 (78.3%) were compatible, and 13 (21.7%) were incompatible. Among 47 compatible results, 30 (63.8%) showed adequate CCI and 17 (36.2%) showed inadequate CCI at 1-hour post-transfusion. Among the incompatible results, 3 (23.1%) had adequate CCI and 10 (76.9%) had inadequate CCI. Significant improvements were found in the mean CCI when comparing cross-matched compatible platelets and incompatible platelets at 1hour or 24 hours (p = 0.009 and p < 0.001, respectively). From the 40 studied patients, HLA alloimmunization was present in 18 patients (45.0%) and absent in the remaining 22 patients (55.0%). In the absence of HLA alloimmunization, patients showed significantly better responses at 1 hour and 24 hours (p = 0.001 and p = 0.015, respectively). There was better sensitivity of platelet crossmatching with random donor platelet concentrates than single donor platelet concentrates. Conclusions: Platelet crossmatching using SPRCA and HLA screening are effective and rapid tools for better management of patients' refractory to platelet transfusions.