RB protein expression and loss of heterozygosity (LOH) in the RB gene were studied in 77 primary lung carcinomas of all histological types. RB protein expression was studied by immunohistochemistry with 3 anti-RB antibodies, and was found altered in 23/29 (79%) neuro-endocrine (NE) carcinomas and in 18/48 (37%) non-NE carcinomas. RB gene allele status was studied with 3 probes detecting RFLP in RB locus. Fifty-five patients were informative, and loss of heterozygosity was detected in 29 (52%) of the corresponding tumors with 1 of the 3 probes used; 89% of the informative NE carcinomas, excluding carcinoids, and only 13% of the non-NE carcinomas exhibited LOH and loss of RB-protein expression. LOH at the RB locus was strongly correlated with the absence of RB protein in malignant NE carcinomas, and this association was strongly correlated with the neuro-endocrine phenotype. Inactivation of the RB protein in primary NE carcinomas, excluding carcinoids, therefore seems to imply in the majority of cases the mutation of one allele and loss of the remaining allele of the RB gene, leading to loss of RB-protein expression. In contrast, RB-protein expression was independent of allele status in non-NE carcinomas and carcinoids.