Hb Yaoundé [beta134(H12)Val-->Ala] is a rare, silent and asymptomatic hemoglobin (Hb) variant. It was previously reported in a Black man from Cameroon, in association with Hb Kenitra [beta69(E13)Gly-->Arg], and was subsequently found and described as Hb Mataro in a sub-Saharan child. To date, Hb Yaoundé has not been described in Caucasian people and molecular studies have never been performed. Here we describe a three-generation Caucasian Portuguese family in whom Hb Yaoundé was found in association with Hb C [beta6(A3)Glu-->Lys] (in the proband) and in a heterozygous state (in the proband's mother). The Hb studies of the proband's hemolysate, performed by isoelectric focusing (IEF) and low-pressure cation exchange chromatography, only revealed an Hb variant identified as Hb C by comparison with a control. However, analysis performed by reversed-phase high-performance liquid chromatography (HPLC) showed two different beta chain variants and a complete absence of the normal beta chain. This uncommon Hb variant was identified as Hb Yaoundé by DNA sequencing analysis of the beta-globin gene (codon 134, GTG-->GCG). The beta-globin gene haplotypes were determined in all family members using polymerase chain reaction (PCR)-based methodology; Hb Yaoundé was found to be associated with the Mediterranean haplotype II. This study is the first description of Hb Yaoundé in Caucasian individuals, and its association with a Mediterranean haplotype supports the hypothesis of an independent genetic origin other than African.