Polymorphic eruption of pregnancy (PEP), formerly known as pruritic urticarial papules and plaques of pregnancy, is a dermatosis of pregnancy that must be distinguished from pemphigoid gestationis (PG). Although this differential diagnosis may be possible on routine histology, an additional biopsy for direct immunofluorescence (DIF) is often needed. Recent studies have demonstrated the utility of anti-C4d or anti-C3d antibodies in the diagnosis of bullous pemphigoid (BP) in formalin-fixed paraffin-embedded tissue (FFPE). We investigated the utility of routine immunohistochemistry (IHC) for anti-C4d in FFPE tissue in the specific differential diagnosis of PEP versus PG in known, DIF-proven cases. We performed C4d IHC on PEP (n = 11), PG (n = 8), DIF-proven BP (n = 12), and other common dermatoses (n = 12) that are typically DIF negative. None of the PEP cases (0/11) or the other common dermatoses (0/12) demonstrated C4d positivity at the basement membrane zone. In comparison, 100% of PG cases (8/8) and 83.3% of BP cases (10/12) showed linear C4d immunoreactant deposition along the basement membrane zone. The results demonstrate the potential utility of C4d IHC in FFPE tissue for distinguishing PEP from PG, thus potentially obviating the need of a repeat biopsy for DIF, particularly in C4d-negative cases where there is a low suspicion of PG on both clinical and histological grounds. Also, patients with positive C4d-positive immunoreactivity may also potentially proceed directly to less invasive serological confirmatory testing, such as BP180 NC16a enzyme-linked immunoabsorbent assay.