Small cell lung cancer (SCLC) is characteristically not associated with tumour‐infiltrating lymphocytes. Since SCLC has been reported to show marked reduction of class I HLA, the reduced expression has been considered a means of escaping anti‐cancer immunity. However, HLA‐DR expressed in cancer cells is now known to contribute to anti‐cancer immunity. To clarify the difference in HLA‐DR expression between SCLC and non‐small cell lung cancer (NSCLC), and the mechanism, the expression and the cis‐ and trans‐acting factors involved were investigated. HLA‐DR was not immunohistochemically detected in any SCLC and could not be induced by interferon gamma (IFN‐γ) in any SCLC cell line, whereas HLA‐DR was expressed to varying degrees and was easily induced in NSCLC. SCLC cell lines lacked class II transactivator (CIITA) even after IFN‐γ induction, whereas NSCLC cell lines expressed CIITA. The other class II HLA‐specific transcription factors were expressed and genomic DNA of HLA‐DR, including the promoter, was conserved well both in SCLC and in NSCLC cell lines. CIITA transfection improved the expression of HLA‐DR in SCLC. In conclusion, the lack of CIITA results in severe deficiency of HLA‐DR expression in SCLC. Since CIITA has also been reported to induce class I HLA, CIITA transfection might make it possible to establish effective anti‐cancer immunotherapy against SCLC through the up‐regulation of class I and class II HLA. Copyright © 1999 John Wiley & Sons, Ltd.