The aim of this work was to investigate the ocular hypotensive activity of some topically administered cAMP-phosphodiesterase inhibitors alone and in combination with dopaminergic compounds. Experiments were performed with ocular normotensive rabbits and during transitory induced ocular hyper- or hypotension. An ocular hypotensive effect was observed after instillation of aminophylline, dyphylline, pentoxifylline, caffeine, and iso-caffeine, but not following topical hydroxypropyl-1,3-dimethylxanthine. Dopaminergic compounds were also studied in order to be combined with phosphodiesterase inhibitors as ocular anti-hypertensive treatment. Significant ocular hypotensive activity was observed after topical application of trifluperidol, fluphenazine, thiothixene, and the S(-) enantiomer of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP). Of the cAMP-phosphodiesterase inhibitors that were tested, pentoxifylline was the most interesting compound, with good ocular tolerance, significant reduction in intra-ocular pressure, and potential retinal microvascular benefits. After allowing adequate time for pentoxifylline to reach its maximal activity, trifluperidol or S(-)-3-PPP was also instilled. A more pronounced ocular hypotensive effect was then observed. The findings of this study may suggest that administration of eye-drops combining drugs acting by separate ways on second messengers involved in the regulation of intra-ocular pressure (e.g. cyclic AMP) could be used to reduce intra-ocular pressure during glaucoma.