Creutzfeldt-Jakob disease and other prion diseases are diseases with yet not well-defined routes of transmission and infection. The safe processing of potentially contaminated tissue material remains a challenge for histologic laboratories. Formic acid pretreatment is considered to be effective in prion inactivation. We evaluated the c-erbB2 and the hormone receptor-status in potentially prion infectious breast cancer tissue after pretreatment with formic acid. Paired breast cancer tissue samples were immunostained with commercially available antibodies against c-erbB2, estrogen receptor, and progesterone receptor with 1 tissue sample of each pair being pretreated with 98% formic acid. Staining was evaluated either according to the HercepTest score or using an immunoreactive score. Additionally, fluorescence in situ hybridization (FISH) analyses were performed for 7 of these cases. Untreated tissues showed strong circumferential staining for c-erbB2 (HercepTest score 3+), whereas the membranous staining of the tissues pretreated with formic acid was significantly weaker. FISH analyses showed no differences in both groups. The hormone receptor expression was not significantly influenced and positivity was maintained in all cases. In breast cancer patients, the pretreatment of tissue with formic acid for prion-decontamination in the case of suspected Creutzfeldt-Jakob disease or other prion diseases can lead to underestimation of the immunohistologically determined c-erbB2 status. In these cases, a c-erbB2-FISH analysis should be performed. For the immunostaining of hormone receptors in breast cancer, formic acid pretreatment can be applied without negative effects on the sensitivity or specificity of the assay.