Pemphigus vulgaris (PV) is a blistering skin disorder mediated by autoantibodies targeting the epidermal adhesion molecule desmoglein 3 (Dsg3). As Th2‐associated cytokines are necessary for directing antibody production, it is hypothesized that Dsg3‐specific Th2 activity is associated with active disease. We used cell‐surface‐matrix technology in combination with flow cytometry to characterize the Dsg3‐reactive T‐cell population using peripheral blood mononucleocytes sampled from PV patients stratified by active (n = 9) or remittent disease (n = 6), and healthy human leucocyte antigen‐matched controls (n = 5). We evaluated interferon‐γ‐producing CD4+ cells (Th1) and interleukin (IL)‐10‐ or IL‐4‐producing CD4+ cells (Th2). The mean frequency of Th2 CD4+ T cells was significantly elevated for five of nine PV patients with active disease. No significant Th2 responses were detected for patients with remittent disease or controls. There was a significant association of Th2 activity with active disease compared with remittent and control groups (P = 0.026 and P =0.012, respectively), and Th2 activity was significantly correlated with anti‐Dsg3 IgG titre (P = 0.044). One patient with remittent disease converted from a Th2‐negative to a Th2‐positive response with the initiation of disease activity. An antigen‐specific CD4− lymphocyte response was detected in five PV patients (36%), and was shown to correlate closely with the CD8+ population. These results are consistent with the hypothesis that Th2 response directs autoantibody production and is therefore associated with disease activity in PV.