Strong HLA‐DR antigen expression on cancer cells relates to better prognosis of colorectal cancer patients, although the precise mechanism is controversial. From an immunological point of view, HLA‐DR antigen, induced by interferon (IFN)‐γ, is required for tumor‐associated antigen recognition by CD4+ T cells. For instance, as reported previously, the expression of HLA‐DR antigen in normal colorectal epithelium immediately adjacent to cancer coincided significantly with the existence of IFN‐γ mRNA in the tissue. From another aspect, IFN‐γ has been revealed to suppress c‐myc expression in vivo through a stat1‐dependent mechanism, which is important for cell growth, cell cycle and chromosome instability. In the present study, strong HLA‐DR‐positive expression on cancer cells was significantly related to better prognosis for colorectal cancer patients. High IFN‐γ mRNA expression in situ indicated significantly less activation of c‐myc mRNA expression. Further, HLA‐DR antigen expression in cancer cells, as well as Dukes stages, was an independent factor for better long‐term survival by multivariate analysis. Taken together, IFN‐γ, which induces HLA‐DR antigens on the cell surface, also suppresses c‐myc expression in situ, and is a possible non‐immunological mechanism involved in the better long‐term survival of colorectal cancer patients. (Cancer Sci 2006; 97: 57– 63)