Hereditary lymphedema is a rare, lymphatic disorder resulting in the chronic swelling of the extremities. It shows wide inter- and intra-familial clinical heterogeneity as well as variability in the age of onset. There are more than four genetically distinct lymphedema conditions known and mutations in three genes have been discovered in families with lymphedema. However, many other familial lymphedemas do not show linkage with the known loci, suggesting genetic heterogeneity. Here, we describe a large inbred Pakistani family with congenital, progressive lymphedema confined to the lower limbs, which fades away at 40-45 years of age. This condition segregates in an autosomal dominant fashion with reduced penetrance. The features are close to primary lymphedema I, Nonne-Milory type (MIM 153100). We exclude this condition for linkage to the known loci for lymphedema by employing highly polymorphic microsatellite markers from these intervals. Then, through a genome-wide linkage study we show that the malformation in our family maps to chromosome 6q16.2-q22.1. The highest pair-wise LOD score (Z(max) = 3.19) was obtained with microsatellite marker D6S1671, and a multipoint score of 3.75 was obtained at 108 cM. Haplotype analysis indicated that the critical interval in this family flanks between markers D6S1716 and D6S303. Mutation analysis in FOXO3, a likely candidate within this interval, did not show any pathogenic change in the affected family subjects. Our study provides an evidence of a second locus for lymphedema type I. The discovery of the underlying gene could be helpful for the understanding of this heterogeneous hereditary condition.