Metal dust inhalation induces an interstitial lung disease which may progress to pulmonary fibrosis (hard metal disease, HMD). Cobalt is believed to be the pathogenic agent of HMD. A strong genetic association of HMD with some HLA-DP alleles has been reported although the role of these molecules in the occurrence of the fibrotic disorder remains unclear. A possible explanation of these findings is that HLA-DP but not other HLA class II molecules can bind cobalt. This could have as a consequence an HLA-DP-mediated specific activation of the immune system. To test this hypothesis, we have set up an in vitro binding assay using 57Co and purified HLA-DP and -DR molecules. The results indicate that HLA-DP but not HLA-DR molecules bind cobalt. Moreover, the presence of HLA-DP Glu beta69, which is associated with susceptibility to HMD, determines a higher metal uptake. Molecular modelling of HLA-DP2 molecules places the Glu beta69 residue in a position relevant in determining peptide specificity. The possibility that binding of cobalt by HLA-DP molecules can interfere with their antigen presenting functions is discussed.