L-Arginine (L-Arg), a substrate for nitric oxide synthase (NOS) at a dose of 250–500 mg/kg, i.p., significantly reduced the duration of immobility both in the forced swimming test (FST) and in the tail suspension test (TST), two models of depression in mice, without changing locomotion in an open field. Paradoxically, a similar effect was observed with the administration of NG-nitro-L-arginine (L-NNA) (0.3–10 mg/kg, i.p.), an inhibitor of NOS. However, higher doses of L-Arg (750–1000 mg/kg) and L-NNA (30 mg/kg) did not produce any antiimmobility effect in FST and TST. The inactive isomers D-Arg (100–1000 mg/kg, i.p.) and D-NNA (0.3–30 mg/kg, i.p.) did not affect immobility duration in either the FST and TST. Preadministration of L-NNA (30 mg/kg, i.p.), but not of D-NNA completely blocked the anti-immobility effect of L-Arg (500 mg/kg, i.p.) in the FST. Similarly, L-Arg (750 mg/kg, i.p.), but not D-Arg blocked the anti-immobility effect of L-NNA (3 mg/kg, i.p.) in the FST. The results indicate that either the synthesis of NO or the inhibition of its synthesis may produce antidepressantlike effects when assessed in the FST and TST. The physiological meaning of this finding is still obscure, but it could indicate that NO has a dual role in the modulation of depression.