Jervell and Lange-Nielsen syndrome (JLNS) is characterized by sensorineural deafness, QT prolongation, abnormal T waves, ventricular tachyarrhythmias, and autosomal recessive inheritance. Previously homozygous mutations in the potassium channel-encoding genes, KvLQT1 (alpha-subunit) and KCNE1 (beta-subunit), have been described in consanguineous families with JLNS. We screened two nonconsanguineous families with JLNS for mutations in KvLQT1, using single-strand conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing. In one family, a missense mutation was identified in exon 6 of KvLQT1 on the maternal side, resulting in a glycine to aspartic acid substitution at codon 269 (G269D). The apparently normal father had an incompletely penetrant missense mutation in exon 3 of KvLQT1, introducing a premature stop codon at position 171. In the other family, a missense mutation resulting in the substitution of asparagine for aspartic acid at codon 202 (D202N) was identified in the mother and maternal grandmother, who had QTc prolongation (borderline in the mother), while the father and paternal grandfather, who were clinically normal, had a deletion of nucleotide 585, resulting in a frameshift and premature termination. In both families, the proband inherited both mutations. In this report we provide evidence that not only homozygous but also compound heterozygous mutations in KvLQT1 may cause JLNS in nonconsanguineous families. Incomplete penetrance in individuals with mutations appears to be frequent, indicating a higher prevalence of mutations than estimated previously. Interestingly, mutations resulting in truncation of the protein appear to be benign, with heterozygous carriers being asymptomatic.