TRALI is a challenging diagnosis for both the transfusion specialist and the clinician. A Canadian consensus panel has recently proposed guidelines to better define TRALI and its implications. The guidelines recommend classifying each suspected case in one of the following 3 categories: (1) "TRALI," (2) "Possible TRALI," or (3) "Not TRALI." We report the clinical presentation, laboratory evaluation, and management of 3 patients with respiratory failure (RF) following allogeneic blood transfusions. These patients all experienced RF within 6 hr post-transfusion. Based on a review of the clinical and laboratory data and applying the Canadian guidelines, the first patient, a 67-yr-old man with chronic myelomonocytic leukemia, was diagnosed as "TRALI" due to the sudden onset of RF requiring intensive resuscitation. The second patient, a 55-yr-old man with aplastic anemia, was diagnosed as "Possible TRALI" due to pre-existing RF that worsened after blood transfusion. The third patient, a 1-yr-old male, was diagnosed as transfusion associated circulatory overload (TACO) and "Possible TRALI," although his RF improved after treatment with diuretics. In all 3 cases, the blood donor center was informed of the suspected TRALI reactions. The remaining blood products from the donors associated with these reactions were quarantined. After review of the clinical data, the donors associated with cases #1 and #3 were screened by the blood center for granulocyte and HLA antibodies. Using a Luminex flow bead array, the following class I and class II antibodies specific for patient #1 were identified in the respective donor: anti-A25, B8, B18, and anti-DR15, DR 17. Subsequently, donor #1 was permanently deferred. A non-specific IgM anti-granulocyte antibody was identified in the donor associated with case #3, and this donor was subsequently disqualified from plasma and platelet donations. In conclusion, the Canadian guidelines to categorize patients suspected of TRALI provide a useful framework for evaluation of these patients and their respective blood donors.