Autoimmune bullous diseases are distressing and sometimes risky bullous dermatoses characterized by the presence of antibodies focused against disease-specific target antigens. Recognition of these antibodies using immunofluorescence is used to be the only sure diagnostic method after reviewing the routine histopathological section. Because of many causes that make the using of immunofluorescence difficult, we tried to evaluate the role of immunohistochemistry in diagnosis of these bullous skin diseases; 40 pemphigus cases (30 pemphigus vulgaris and 10 pemphigus foliaceus) and 37 non-pemphigus cases (35 vesiculobullous skin diseases and 2 normal skin). Skin biopsy was obtained for histopathological diagnosis, immunofluorescence study, and immune-histochemical studying for IgG4 and C3d expression. IgG4 was positive in almost all cases of pemphigus vulgaris and most of pemphigus foliaceus and bullous pemphigoides, while all other diseases were negative. C3d expression was positive in almost all bullous pemphigoides and pemphigus gestationis cases, while it was negative in almost all other cases. Sensitivity and specificity of both markers increase by using them in combination in diagnosis of such bullous diseases. IgG4 and C3d immunohistochemistry could replace DIF in almost all of our cases, so before doing DIF, reliable immunohistochemical detection of IgG4 and C3d on formalin-fixed tissue is advised to be done.