Bullous pemphigoid is a subepidermal blistering disease associated with auto-antibodies (auto-ab) to BP180 and BP230. We developed ELISAs utilizing baculovirus-encoded recombinant proteins of BP230 and BP180 and studied their diagnostic and prognostic values by assessing the profile of the auto-ab response in 127 patients with BP. 39 patients had focal involvement, whereas 88 had generalized disease; 51 individuals served as controls. The results indicate: (1) BP180 IgG reactivity was associated with an overall sensitivity of 0.953 and specificity of 0.940; (2) 105 of 127 BP patients also displayed BP230 auto-reactivity, the global diagnostic performance of which, however, was moderate compared to BP180-auto-reactivity (sensitivity 0.815 vs 0.953, specificity 0.648 vs 0.940); (3) 101 patients (79.5%) had concordant BP180 and BP230 reactivity; (4) the association between the presence of BP230 auto-reactivity and focal involvement was stronger than in generalized disease (odds ratio (OR) 17.7 vs 10.2), independently from BP180 auto-ab profile; (5) correlation of total IgG with IgG₁ and IgG₄ was variable for both BP180 and BP230. Collectively, the global diagnostic properties of the BP180-ELISA outperform those of the BP230-ELISA. Presence of BP230 auto-reactivity, however, supports the diagnosis of BP and might be indicative for the extent of the disease.