Thiazolidinedione drugs are in widespread use for the treatment of type 2 diabetes. In addition to improving insulin sensitivity, they generally result in a modest elevation of plasma HDL cholesterol. We report three patients, all of whom had preexisting diabetic dyslipidemia, who showed a profound reduction in plasma HDL cholesterol and apolipoprotein AI levels soon after the initiation of rosiglitazone therapy. In all three patients, HDL cholesterol levels returned to normal following drug withdrawal. The fact that this phenomenon was not seen in >1,400 patients studied in clinical trials indicates that it is likely to be rare and idiosyncratic. Until the frequency of this adverse reaction is clearer, it would seem advisable to ensure that plasma HDL cholesterol is documented before and rechecked after commencement of thiazolidinedione therapy.