A female child was born after an uncomplicated pregnancy and diagnosed to have HbS trait. Both parents are healthy; mother is of Sardinian/Portuguese descent, and father is of English/Irish/German ancestry. She had a few episodes of musculoskeletal pain. At age 4 years, she developed severe abdominal pain. She was felt to have appendicitis; a rectal contrast CT scan was negative. Hb was 80 g/L, MCV 82 fL, WBC 16.7xiO'/L, and granulocytes 6.5x109/L. She underwent laparotomy and appendectomy. The appendix was normal. Post-operatively, she developed increasing respiratory distress, hypoxia, and rapidly progressive pulmonary infiltrates on X-ray. Her clinical picture was felt consistent with acute chest syndrome. A red cell transfusion was given. She improved slowly, was given pneumococcal and meningococcal vaccines, and started on penicillin prophylaxis. She continues to do well. Her blood smear revealed sickle cells, schistocytes, target cells, and Howell-Jolly bodies. Hb electrophoresis revealed 39% HbS and 58% HbA. Isoelectric focusing showed only HbA and HbS. DNA was extracted from peripheral blood leukocytes, the β-globin gene region was amplified by polymerase chain reaction (PCR), and direct nucleotide sequencing was done on the PCR product. She was shown to be a compound hétérozygote for HbS (βcodon 6 Glu→Val) and Hb Quebec-Chori (β87 Throne) Hb Quebec-Chori interacts with Hb S and promotes Hb polymerization upon deoxygenation. This hemoglobin was first described in a three-year-old girl who had identical β-globin genotypes to our patient, and a similar clinical presentation. It is indistinguishable from HbA by electrophoresis and isoelectric focusing, and this led to the incorrect diagosis of HbS trait. There are at least two other mutant hemoglobins that might cause similar diagnostic problems. Compound heterozygotes for HbS and HbS-Providence or Hb Arlington Park may be misdiagnosed as HbS trait because these hemoglobins have similar electrophoretic mobility to HbA. These patients also can have sickling episodes. Unusual combinations of globin gene mutations are now increasingly identified. This case highlights the need for careful consideration of all clinical and laboratory findings so that appropriate tests, including DNA-based genotyping, can be performed to allow correct diagnoses to be made and ensure proper care and genetic counseling for affected patients and families.