Based on open studies. D-penicillamine (DPA) has been used for the treatment of systemic sclerosis (SSc) but we believe the controlled trial of this drug in SSc does not support its use to treat this disease. Open trials are inevitably biased by selection bias and randomized, blinded, controlled studies are required to minimize both known and unknown confounding variables. The high vs. low dose DPA trial was a well-controlled, randomized, double-blind study which met criteria for a high quality study, although it was not placebo-controlled. Toxicity was increased in the high dose group, thus showing a biologic response, although the study showed no clinical efficacy differences between a mean dose of 120mg DPA every other day (equivalent to 60mg qd) and a mean dose of 822mg DPA daily. One might argue that 60mg DPA is effective, but we believe this is highly unlikely, as doses significantly higher than this have been shown to be ineffective in other connective tissue diseases such as rheumatoid arthritis. In our opinion. D-penicillamine is, unfortunately, ineffective in treating early, diffuse, systemic sclerosis.