The molecular basis of disease heterogeneity in autoimmune conditions such as Pemphigus vulgaris is poorly understood. Although desmoglein 3 (Dsg3) has been well established as a primary target of immunoglobulin (Ig) autoantibodies in PV, there remain several questions regarding the overall distribution of anti-Dsg3 Ig subtypes among patient subsets and considerable controversy regarding whether an isotype switch can be observed between phases of disease activity. To systematically address the outstanding questions related to Ig-isotype specificity in PV, we analyzed IgA, IgM, IgG1, 2, 3 and 4 anti-Dsg3 levels by ELISA in 202 serum samples obtained from 92 patients with distinct clinical profiles based on a set of defined variable (activity, morphology, age, duration) and constant (HLA-type, gender, age of onset) clinical parameters, and 47 serum samples from HLA-matched and -unmatched controls. Our findings provide support for earlier studies identifying IgG4 and IgG1 as the predominant antibodies in PV with significantly higher levels in active than remittent patients. We do not see evidence for an isotype switch between phases of disease activity and remission, and both IgG4 and IgG1 subtypes remain elevated in remittent patients relative to controls. We do, however, find IgG4 to be the sole subtype that further distinguishes PV patient subgroups based on different disease morphologies, disease duration, and HLA-types. These data provide further insight into the immune mechanisms responsible for phenotypic expression of disease, and contribute to the broader effort to establish comprehensive immunoprofiles underlying disease heterogeneity to facilitate increasingly specific and individualized therapeutic interventions.