Tamoxifen, a widely used anti-cancer agent, is now also used for healthy women with risk of breast cancer. Furthermore, it is the prototype of the "selective estrogen receptor modulator" family, with promise for neuroprotection. However, possible effects on neurotransmission have been little explored. Recently, tamoxifen was shown to potentiate chloride responses to low concentrations of exogenous glycine in cultured spinal neurons from rat embryo. The present study investigates the possible modulation by tamoxifen of the spontaneous synaptic glycinergic activity recorded from voltage-clamped hypoglossal motoneurons, using the whole-cell patch-clamp technique in brain stem slices from juvenile rat. Miniature currents were isolated with tetrodotoxin. Tamoxifen increased the mean amplitude of glycinergic miniature currents, by 68-79% at 2 µM (in 9/10 cells) and by 47% at 0.5 µM (in 4/9 cells). Furthermore, tamoxifen markedly increased the frequency of glycinergic miniatures, by a factor reaching 15 in some neurons, even in the presence of the Ca²⁺ channel blocker Cd²⁺. Tamoxifen also increased the frequency of the total spontaneous glycinergic activity without tetrodotoxin. The increase in miniature amplitude is consistent with the increase in postsynaptic glycine receptor sensitivity previously reported. The increase in frequency indicates an additional presynaptic effect. Addition of exogenous glycine could also increase the frequency of glycinergic miniatures. Thus, one of the presynaptic effects of tamoxifen might be potentiation of the basal activity of presynaptic glycine receptors facilitating glycine release. Possible risks related to modulation of glycinergic neurotransmission by tamoxifen should be considered when recommending its use in healthy individuals.