The immunohistochemical expression of thyroid transcription factor-1 (TTF-1) was investigated in various cytological subtypes of primary lung adenocarcinoma, with special reference to intratumoral heterogeneity. Three groups were categorized according to cytological subtype: group A, adenocarcinomas with either a Clara cell and/or type II epithelial cell component (Clara/type II) or a mixed Clara/type II and bronchial surface epithelial cell component (BSE) (mCB), in addition to other components; group B, adenocarcinomas with components including either BSE, a goblet cell component (GOB) or a mixed BSE and GOB component (mBG), and lacking Clara/type II or mCB; group C, adenocarcinomas with only a poorly differentiated component (POR). In group A all Clara/type II, mCB, BSE and the majority of POR were TTF-1 positive. In group B the majority of BSE, POR and all GOB were TTF-1 negative. BSE and POR in both groups had a different phenotype, possibly reflecting their different natural history. In group C 80% of cases were TTF-1 positive, suggesting that the majority were derived from group A tumors.