Identifying patients with germline MUTYH mutation-associated polyposis is presently difficult. The aim of this study is to investigate the possibilities of IHC as a screening test to select patients for MUTYH mutation analysis. The expression of MUTYH protein in colorectal adenomas or cancer was studied by IHC using three different (1 polyclonal and 2 monoclonal) antibodies in six samples from patients with biallelic MUTYH mutations, in three samples from patients with a single MUTYH mutation, and in 11 samples from patients without MUTYH mutations. With the polyclonal antibody, adenomas and carcinomas from patients with biallelic MUTYH mutations showed a strong supranuclear cytoplasmic staining without epithelial nuclear staining. The strong supranuclear staining was also observed in the three samples from patients with a single MUTYH mutation and in nine out of 11 samples from patients without MUTYH mutations, with or without nuclear staining. Samples incubated with the monoclonal antibodies showed a non-specific pattern. Our results demonstrate that, in contrast with previous data, the cytoplasmic staining in neoplastic cells does not discriminate MUTYH mutated from unmutated cases. At present, IHC cannot be used in clinical practice to differentiate between colorectal tissue with and without germline MUTYH mutations.