A series of substituted 4-aryltetrahydrothieno[2,3-c]pyridines was prepared by acid-catalyzed cyclization of 1-aryl-2-[(2-thienylmethyl)amino]ethanol derivatives. The compounds were examined for their antidepressant activity, as demonstrated by their ability to inhibit the uptake of norepinephrine (NE) and serotonin (5-HT) and to prevent tetrabenazine-induced ptosis (TBZ) in mice. Significant inhibition of both neurotransmitters is observed for several of the tested compounds, while some of them are selective inhibitors of either NE or 5-HT uptake. Optimal activity is associated with the introduction of lipophilic substituents into the 4-position of the phenyl ring and less lipophilic substituents into the 2-position of the thiophene ring (11, 23). Compound 33 bearing substituents in positions 2 and 6 of the phenyl ring is inactive. This might be a consequence of an out of plane conformation of this compound.