Tianeptine is a novel anti-depressant with an efficacy equivalent to that of classical anti-depressants. Additional beneficial effects include neuroprotection, anti-stress and anti-ulcer properties whose molecular mechanisms are still not completely understood but may involve changes in the anti-oxidant defence system. Herein, we have studied the effects of tianeptine on both contractile activity of isolated rat uteri and components of the endogenous anti-oxidative defence system. Tianeptine-induced dose-dependent inhibition of both spontaneous and Ca2+-induced contraction of uterine smooth muscle. The effect was more pronounced in the latter. Tianeptine treatment increased glutathione peroxidase (GSH-Px) and catalase (CAT) activities in spontaneous and Ca2+-stimulated uteri. A significant decrease in glutathione-reductase (GR) activity in both spontaneous and Ca2+-induced uterine contractions after tianeptine treatment indicated a reduction in reduced glutathione and consequently a shift toward a more oxidised state in the treated uteri. In spontaneously contracting uteri, tianeptine caused a decrease in copper-zinc SOD (CuZnSOD) activity. Tianeptine's anti-depressant effects may be accomplished by triggering a cascade of cellular adaptations including inhibition of smooth muscle contractility and an adequate anti-oxidative protection response.