We describe a patient who presented with polyarthritis, pleurisy, rash, and a positive antinuclear antibody result after 5 years of D-penicillamine therapy. D-penicillamine-induced antinuclear antibodies were mainly high-titer IgG directed against the (H2A-H2B)-DNA complex. Weak IgM activity with H1 and H2B was also observed. Withdrawal of D-penicillamine therapy resulted in improvement in clinical symptoms and gradual resolution of serologic abnormalities.