Thromboxane A2 (TXA2) is a short-lived metabolite of the fatty acid arachidonate that is formed upon platelet activation; it stimulates platelet responses including shape change, aggregation and secretion of granule contents. The TXA2 pathway of platelet activation is important clinically as demonstrated by the beneficial effect of aspirin, that inhibits TXA2 formation, in preventing arterial thrombotic events. TXA2 elicits its stimulatory responses on platelets by binding to the G protein-coupled thromboxane prostanoid (TP) receptor (approximately 55 kD). Of the α and β isoforms of the TP receptor that have been identified, TPα appears to be the predominant form expressed in platelets, utilizing Gq and G12 in signaling. There have been reports of inherited platelet function disorders involving the TXA2 pathway of platelet activation, and the best characterized is a single amino acid substitution (Arg60 → Leu) in the first cytoplasmic loop of the TPα receptor in a dominantly-inherited bleeding disorder characterized by a defective platelet response to TXA2. Here, we describe a pediatric patient with an inherited platelet defect in the TXA2 pathway that does not appear to involve a mutation in the TPα receptor. The 10 year-old patient and his mother (but not his father) have significant bleeding histories involving recurrent epistaxis (patient) and severe menorrhagia with chronic iron deficiency (mother). Platelet counts of both son and mother are in the normal range. Consistent findings with platelet aggregation testing were prolonged lag phases with collagen, decreased (mother) to minimal (patient) responses with arachidonate and shape change only with the stable TXA2 mimetic U46619. PFA-100 closure times were prolonged with the aspirin-sensitive collagen/epinephrine cartridge: >271 sec (patient), 222 sec (mother) (upper limit of normal: 163 sec for children, 142 sec for adults), but normal with the collagen/ADP cartridge: 97 sec (patient), 85 sec (mother) (upper limit of normal: 111 sec for children and adults). Dense granule counts, determined by whole mount electron microscopy, were slightly lower than normal for both the patient (2.3/platelet) and his mother (2.8/platelet) (normal range: 3–7/platelet). Western blotting utilizing the polyclonal P2 rabbit anti-human TP receptor antibody showed the presence of an approximately 55 kD band in both subjects. Fresh platelets from the patient’s mother were available for flow cytometric analysis with the P2 antibody; mean fluorescence intensity of P2 binding for the patient’s mother’s platelets was 67.6 compared with 60.4 for platelets from a healthy control. Analysis of the TPα receptor gene of the patient indicated a heterozygous synonomous substitution C795T in Ile265 of the sixth transmembrane domain; this substitution was not present in the mother. Taken together, these results suggest a dominantly-inherited platelet function disorder involving the TXA2 pathway of platelet activation. The presence of a normal TPα receptor gene and normal levels of the TPα protein indicate the likelihood of a downstream TXA2-signaling defect.