Sulfasalazine (SSZ) can induce serological and clinical autoimmune reactions but the occurrence of SSZ-related Wegener's granulomatosis (WG) has not been reported before. We describe two patients with rheumatoid factor (RF)-positive rheumatoid arthritis (RA) who developed biopsy-proven WG with serious organ involvement during SSZ therapy. The pathogenetic mechanism that explains the relationship between SSZ and the occurrence of a de novo anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis or a flare is discussed. We propose that WG can be a rare complication of SSZ therapy and that this, like other autoimmune adverse events of this drug, is mediated by SSZ-induced apoptosis.