Activation of sigma-1 receptors (Sig-1R) reportedly has antidepressant-like action. Limited data suggest that Sig-1Rs also modulate anxiety-related behaviors. The present experiments measured depressive-like, anxiety-like and motor behavior in Sig-1R knockout mice and their wildtype littermates. Sig-1R knockout mutants showed increased immobility in the forced swimming test, a depressive-like phenotype, but normal anxiety-like behavior in the elevated plus-maze and light/dark box tests and normal locomotor activity. The results further suggest that Sig-1Rs inversely modulate depressive-like behavior.