A method originally developed to detect topoisomerase DNA complexes has been adapted to determine DNA‐protein cross‐links formed in cells following their exposure in vitro and in vivo to cross‐linking agents. A preliminary study on welders and controls has been carried out to assess the feasibility of this assay to detect human exposure to chromium (Cr) and nickel (Ni) that are associated with increased DNA‐protein cross‐links. The percentage of cross‐link was significantly higher among welders (1.85% ± 1.14) than among controls (1.17% ± 0.46; p = .01) Cross‐links were not affected by age, weight, or smoking status. The assay developed has substantial advantages over previous methods, being considerably more simple, inexpensive, and sensitive.