The co-existence of Hemoglobin H (Hb H) disease and heterozygosity for β-chain structural variants is a rare occurrence. Hb H disease has been reported in conjunction with Hb E, Hb C, Hb S, and Hb Hamilton. The combination of Hb H disease with Hb C and Hb S reportedly results in a mild hemolytic anemia without detectable Hb H. We present a new case of atypical Hb H disease that was also heterozygous for the rare β-chain variant Hb Raleigh. The patient is a 27-year-old Cambodian female referred for the evaluation of microcytic anemia unresponsive to iron. She had a lifelong history of generalized fatigue, exertional dyspnea, and weakness in her legs. Physical exam was unremarkable except for pallor of mucuous membranes. There was no hepatosplenomegaly. She had a Hb of 9.7, HCT 30.8, MCV 56, MCH 17.6, MCHC 31.5, ferritin 92. Hb analysis on IEF revealed Hb A, Hb A2, and an abnormal band slightly more anodic to Hb A. No Hb H was observed. On cation exchange HPLC, she had 49.7% Hb A, 48.1% Hb X, and 2.2% Hb A2. Reverse phase HPLC revealed a βx chain eluting immediately before βA. Oxygen affinity was slightly reduced. PCR amplification and sequencing of the β-globin gene revealed heterozygosity for Hb Raleigh (Exon 1, codon 1, GTG→GCG, VAL→ALA). The patient was also found to be a compound heterozygote for -α3.7 and --SEA deletions. This case represents a novel interaction of a structural β-chain variant with Hb H disease. Hb Raleigh has previously been reported in Caucasians and in two Swedish families. It has decreased oxygen affinity. This is the first report of this variant in a Cambodian population. The absence of any detectable Hb H likely results from the inability of variant β-chains to form a viable tetramer with a resultant decrease in βA. The low oxygen affinity did not negatively impact on the degree of anemia. This case, like some others reported previously, shows that the accurate diagnosis of Hb H disease in association with structural β-chain variants can be established by molecular methods, and the detection of Hb H on electrophoretic and chromatographic analyses may not always be reliable.