Abstract Background To predict the effectiveness of topical glaucoma medications based on initial uniocular and binocular treatment. To test a traditional hypothesis that effectiveness following a uniocular trial is associated with the change in IOP in the initially treated eye minus the change in the initially untreated eye. To determine whether uniocular or binocular treatment trials are superior. Methods Based on a review of medical records, we identified 168 instances in 154 patients with bilateral primary open angle glaucoma of initial uniocular use of a topical glaucoma medication with well-documented intraocular pressure (IOP) readings at baseline (IOPA), during the trial (IOPB), and at follow-up (IOPC). Abstracted data included demographic data, IOP, and medication use. Predictors of the IOP following the trial (IOPC) in each eye were identified by multivariable linear regression. In 70 cases, the predictive ability of initial uniocular and binocular treatment could be directly compared. Results In a multivariable analysis, the follow-up pressure in the initially treated eye (IOP1C) was directly correlated with treated eye IOP during initial uniocular use (IOP1B, p < 0.001). In a multivariable analysis, the follow-up pressure in the initially untreated eye (IOP2C) was directly correlated with its baseline IOP2A (p < 0.001), and also tended to be associated with treated IOP1B (p = 0.07). The multivariable regression coefficient (b) for the IOP change in the initially untreated eye was generally not close to the value of -1 expected by the classic teaching (for eye 1, b = 0.04, p = 0.35; for eye 2, b = 0.07, p = 0.50). In 70 cases, the uniocular and binocular trials predicted a similar fraction of the variance in follow-up IOP1C (r2 = 0.56 and 0.57, respectively) and IOP2C (r2 = 0.39 and 0.38, respectively). Conclusion 1) For uniocular trials, the IOP change in the untreated eye should not be subtracted from that in the treated eye. 2) Uniocular and binocular trials have similar predictive value when interpreted correctly. Either may be selected based on clinical circumstances.