Overexpression of the epidermal growth factor receptor (EGFr) has been implicated in the pathogenesis of a wide variety of human malignancies and may be related to asbestos-induced carcinogenesis. Overexpression of the EGFr can be detected immunologically by quantitation of the extracellular domain (ECD) in the extracellular fluid in vitro and in serum in vivo. An enzyme-linked immunosorbent assay (ELISA) for the EGFr ECD was used to examine banked serum samples of 38 asbestosis patients who subsequently developed cancer, 72 age-sex-race-smoking-asbestos exposure matched asbestosis controls without cancer, and 20 age-sex-race-smoking matched nonasbestosis noncancer controls. The mean serum level for the EGFr ECD in the cancer cases (636 +/- 299 fmol/ml) was statistically significantly elevated (P < 0.05) in comparison to the mean level in the asbestosis controls (546 +/- 147 fmol/ml) or the nonasbestosis controls (336 +/- 228 fmol/ml). Defining a positive elevation of the serum EGFr ECD as any value more than 2 standard deviations above the nonasbestosis control mean, 7 (18%) of the cancer cases were positive compared to 4 (6%) of the asbestosis controls and one (5%) of the nonasbestosis controls. In addition, all of these cancer cases had positive serum samples prior to the time of disease diagnosis (average = 5.1 years). These results suggest that serum EGFr ECD may be elevated at an early stage of carcinogenesis in some asbestosis patients and that further prospective study of the utility of this biomarker is warranted.