Abstract Type XVII collagen ( COL 17) and the non‐collagenous 16A ( NC 16A) domain is regarded as the major pathogenic domains for bullous pemphigoid ( BP ). Some patients with BP have autoantibodies against parts of COL 17 outside the NC 16A domain (hereinafter the non‐ NC 16A domain) and show less inflammatory manifestations. There were no significant differences in titres and IgG subclasses between NC 16A‐ BP and non‐ NC 16A‐ BP as determined by indirect immunofluorescent microscopy. The neutrophil activation capacities determined by ROS release did not differ between NC 16A‐ BP and non‐ NC 16A‐ BP . However, NC 16A‐ BP IgG depleted COL 17 in a dose‐dependent manner. Treatment with NC 16A‐ BP IgG, but not with non‐ NC 16A‐ BP IgG, significantly decreased the adhesion strength. We speculate that the differences in clinical severity between NC 16A‐ BP and non‐ NC 16A‐ BP relate to the degree of COL 17 depletion.