Immunologic investigation of a patient with essential (γG-γM) cryoglobulinemia was performed before and after a six-month course of oral treatment with penicillamine. Marked reductions in the amount of cryoprecipitation and in the levels of serum immunoglobulins (γG, γA and γM) were the most striking effects of this therapy. Moreover, there was a reversal in the ratio of γG to γM molecules in the cryoprecipitate; prior to treatment, the γG:γM ratio was 1:2 and after, 7:1. These immunologic changes suggest that penicillamine suppressed the synthesis of γG, γA, and γM, although it appeared to preferentially suppress the cryoprecipitable γM. Despite the immunologic response to penicillamine, the patient's symptoms did not im prove. Persistence of symptoms may be explained by the irreversible peripheral vascular disease existing prior to therapy.