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The reproducibility of the histopathological diagnosis of pleural malignant mesothelioma (MM), after supplementing routine H&E stain by immunohistochemistry (IH) in 77 cases of original diagnoses of MM, was assessed by examining interobserver variation between five pathologists. A battery of commercial antibodies (cytokeratins, vimentin, HMFG-2, anti Leu-M 1 [CD15], BerEP4, B72.3 [TAG-72], carcinoembyonic antigen), considered to be useful in enhancing diagnostic accuracy, was used. The number of definitively classified tumors (accepted MM plus rejected MM) increased from 57 on H&E stain to 60 after IH, with 59 (76.6%) cases being accepted as true MM. Based on IH, the chance-adjusted interobserver agreement was poor (κw = 0.29) and lower than that observed on previous H&E alone. The intraobserver agreement for four of the five pathologists was rather good (κw = 0.54–0.56). The inter- and intraobserver concordance was higher in accepting than excluding the cases as MM. A larger number of cases were classified by all reviewers as mixed or sarcomatous variants after IH. In the interpretation of each immunostain, x values ranged from 0.19 for B72.3 to 0.62 for HMFG-2, which were respectively the least and the most consistently interpreted immunostains. The information additionally contributed by IH did not seem to change the pathologists' diagnoses very much in comparison with those made by routine H&E stain. Until highly specific and sensitive probes for the positive identification of MM become available, a careful scrutiny of routinely stained preparations still remains the most rewarding component of the diagnostic pathway.