Soluble class I major histocompatibility antigens (sHLA), beta 2-microglobulin (beta 2-M), and soluble interleukin-2 receptor (sIL-2R), are secreted by B and T lymphocytes upon activation, and have been used as markers of immune activation in several diseases. Thirty-two Graves' disease patients were randomly assigned to three methimazole (MMI) regimens of treatment: (1) low-dose, starting with 45 mg/day, and lowering the dose thereafter to maintain normal serum thyroid hormones; (2) MMI 60 mg/day + levothyroxine, and (3) MMI 30 mg/day + levothyroxine. Serum sHLA, beta 2-M, sIL-2R, TSH receptor antibodies (TSH-R Ab), T3, and free T4 (fT4) were measured at diagnosis and at weeks 4, 12, and 24 (end of treatment). Patients were followed-up after treatment for at least 24 weeks (24 to 89). At diagnosis, serum levels of sIL-2R, beta 2-M, sHLA, and TSH-R Ab were elevated. Serum sIL-2R, beta 2-M, sHLA, and TSH-R Ab decreased with treatment. No effect of the varying MMI regimens on these parameters was observed. Soluble IL-2R correlated positively with T3, fT4, beta 2-M, sHLA, and TSH-R Ab. Statistically significant, but weak, correlations (r < 0.35) were observed between beta 2-M, sHLA, and TSH-R Ab, between beta 2-M, T3, and fT4, and between TSH-R Ab and T3. Recurrence rates were not associated either with the MMI regimen or any of the parameters studied, with the exception of elevated initial TSH-R Ab levels. Serum sHLA, beta 2-M, and sIL-2R are increased in untreated Graves' disease, and decrease during treatment. No MMI dose-related differences were observed in these parameters, and in the recurrence rate. Unfortunately, sHLA, beta 2-M, and sIL-2R were not useful predictors of prolonged remission after MMI treatment.