An estrogen receptor-negative, multidrug-resistant MDA-MB-A1 human breast cancer cell line was grown in culture with and without a noninhibitory concentration (0.5 microM) of tamoxifen for 122 days. Tamoxifen-treated and control cells were inoculated into opposite flanks of nine nude mice, where they produced measurable tumors in every case. Six of the animals were treated with tamoxifen at 500 micrograms/day for 22 days. Although no inhibitory nor stimulatory effect of tamoxifen was seen in vitro, tamoxifen had a clear tumor-growth-stimulating effect in mice. The most pronounced stimulatory effects were observed in the cells that had been cultured with tamoxifen. Within 3 weeks of the start of tamoxifen therapy, the cells grown in the presence of tamoxifen produced tumors with a mean size of 380 mm2, whereas the cells not pretreated with tamoxifen had tumors of 220 mm2. In contrast, in mice not receiving tamoxifen, the sizes of the tumors were 190 and 140 mm2, respectively. These preliminary results suggest that prolonged in vitro tamoxifen exposure induces cellular changes that result in tumors that are stimulated to grow faster in mice following tamoxifen treatment.