ABSTRACT Background Pemphigus vulgaris (PV) is caused by immunoglobulin G (IgG) autoantibodies targeting desmoglein 3 (Dsg3) and/or desmoglein 1 (Dsg1). While antibody concentration is routinely used to assess disease activity, the role of antibody avidity in PV monitoring has not been elucidated. Methods Sixty‐three consecutive, newly diagnosed, treatment‐naïve patients with PV were enrolled in this retrospective‐prospective study. PV severity was assessed using the Pemphigus Disease Area Index (PDAI) and classified as mild (≤ 15), moderate (> 15, ≤ 45), or severe (> 45). Anti‐Dsg3 and anti‐Dsg1 IgG antibodies' concentration and avidity were determined using conventional and urea‐modified enzyme‐linked immunosorbent assay (ELISA), respectively. Thirty‐three patients were re‐evaluated at the beginning of clinical remission. Receiver operating characteristic (ROC) curve analyses were used to determine optimal cut‐off values and odds ratios (ORs) for anti‐Dsg3 concentration and avidity to distinguish active disease from remission, and mild from moderate‐to‐severe disease. Results Anti‐Dsg3 avidity showed a stronger correlation with PDAI ( r = 0.474, p < 0.001) than anti‐Dsg3 concentration ( r = 0.363, p = 0.004). Anti‐Dsg1 concentration correlated with PDAI ( r = 0.476, p = 0.001), while anti‐Dsg1 avidity did not ( r = 0.216, p = 0.141). Anti‐Dsg3 avidity was a better marker of disease severity than anti‐Dsg3 concentration ( p = 0.003 vs. p = 0.014). Among 13 patients in remission who were still anti‐Dsg3‐positive, avidity decreased more significantly than concentration ( p = 0.007 vs. p = 0.016). Avidity cut‐off of 25.46% distinguished active disease from remission (OR = 3.48), and avidity 35.02% threshold differentiated mild from moderate/severe disease (OR = 6.36). Conclusions This is the first study to assess the correlation between PDAI and anti‐Dsg3/anti‐Dsg1 avidity. Anti‐Dsg3 avidity showed the strongest positive correlation with PDAI, announcing the role of antibody avidity as a valuable biomarker in monitoring PV activity.