Glaucoma, one of the leading causes of blindness, is associated with high intraocular pressure (IOP) as a risk factor. The aim of this study was to examine both local and systemic effects of chronic topical administration of the synthetic CB1/CB2 agonist, WIN-55-212-2 and its potential to sustain ocular hypotension. WIN-55-212-2 (0.5%) or Tocrisolve™, the vehicle, was administered topically three times daily to rats with surgically created glaucoma for 4 weeks, followed by a 1-week washout period. IOP, blood pressure and heart rate were measured weekly along with confocal microscopy and slit lamp biomicroscopy to detect ocular toxicity. IOP decreased rapidly by up to 47% in the WIN-55-212-2 treated group from 14.1±0.7 to 6.6±0.2 mmHg. The decrease was maintained during the treatment period. After the washout period, IOP (12.3±0.2 mmHg) was not different from baseline. In the contralateral eye, IOP showed a downward trend. Tocrisolve™ alone had no effect on IOP. No changes in blood pressure, heart rate or indicators of ocular toxicity were noted within either group. Topical application of WIN-55-212-2 significantly deceased IOP for duration of treatment. The decrease was sustained without the development of tolerance. Following cessation of therapy, IOP rapidly returned to baseline. No significant cardiovascular effects or ocular toxicity were noted during chronic topical therapy with either drug or vehicle.