Atopic dermatitis (AD) results from strong genetic and environmental interactions. AD shows genetic linkage to Chromosome 1q21. This region contains the epidermal differentiation complex (EDC), which consists of genes that form essential components of epidermal surfaces. Filaggrin (FLG) is one of these. Mutations in FLG/(R501X and 2282del4) are reported to be strongly associated with AD and to influence asthma accompanying AD. We investigated these effects in families recruited through a child with severe AD. We genotyped two panels of families, totalling 426, containing 990 affected and unaffected children. We found significant associations with AD (P=0.0001), asthma (P=0.006), and atopy (P=0.002). The FLG mutations were present in 26.7% of patients with AD, but were also present in 14.4% of children without AD. They were weakly associated with disease severity. The variants were not independently associated with asthma. The overall LOD score for genetic linkage of markers to the region was 3.57. This fell to 2.03 after accounting for the FLG mutations, indicating the presence of other genetic variants influencing AD at this locus. Our results provide further confirmation of the importance of mutations in FLG and the skin barrier in AD pathogenesis. The results indicate that investigations of other genes within the EDC should be undertaken.