BACKGROUND:The use of crossmatch-compatible platelets (PLTs) improves posttransfusion corrected count increments (CCIs) in patients with alloimmune PLT refractoriness. However, few reports address the efficacy of utilizing this strategy for patients requiring intensive PLT transfusion therapy lasting several weeks to months. STUDY DESIGN AND METHODS: Medical records of patients with two or more PLT crossmatch assays performed between 2002 and 2010 were reviewed. All patients were refractory to random single-donor apheresis PLT units, defined as two consecutive 1-hour posttransfusion CCIs of less than 7500. A commercial solid-phase adherence assay was used for crossmatching. RESULTS: Seventy-one patients were included. A median of four crossmatch assays were performed per patient (range, 2-17). Mean percent reactivity in initial (58.6%) versus last (55.3%) crossmatch assay for each patient demonstrated no trend toward progressive alloimmunization (p = NS). A total of 738 crossmatched PLT units were administered with a mean Ϯ standard deviation CCI of 7000 Ϯ 7900 (n = 443 units with adequate 1-hr posttransfusion counts), a significant improvement over random PLTs (p < 0.001). Patients with an initial crossmatch reactivity of greater than 66% were significantly more likely to demonstrate at least one panreactive crossmatch assay, impacting the availability of compatible PLTs for optimum transfusion support. One patient (1.4%) developed WHO Grade IV bleeding. CONCLUSIONS: Progressive alloimmunization to mismatched antigens does not impact medium-term transfusion support with crossmatched PLTs. Increased reactivity in the initial crossmatch assay can serve as a trigger to initiate workup for HLA-matched PLTs as a second-line approach. However, for most patients, medium-term transfusion support with crossmatched PLTs offers an effective and rapid first-line approach to management of PLT transfusion refractoriness.