The effects of 2-methoxyestradiol (2ME), a naturally occurring mammalian metabolite of 17beta-estradiol, on adipocyte growth has been investigated in mouse brown adipose tissue precursor cells developed in primary culture. 2ME inhibits brown adipocyte proliferation in a dose-response manner (IC50 = 1.7 x 10(-6) M for DNA synthesis), with much higher potency than its hormone precursor 17beta-estradiol, and cells acquire the typical differentiated morphology--more round with a higher content of triglycerides. 2ME causes similar effects in the immortal brown adipocyte tumor-derived hibernoma cell line HIB 1B and the immortal 3T3-F442A white adipocyte line. These findings suggest a possible role for 2ME in adipocyte proliferation, and probably in the differentiation process, entering the cells in the adipogenic program.