© 2015 Royal Australian and New Zealand College of Ophthalmologists. Background: The aim of this article was to study the circadian intraocular pressure (IOP)-related effects of ocular hypotensive medications using a contact lens sensor (CLS). Design: This is a university-based prospective, randomized, crossover trial. Participants: A total of 23 patients with primary open-angle glaucoma participated. Methods: Patients underwent ambulatory recording of IOP-related patterns for 24h in one eye during 3 monthly sessions using a CLS. Patients were untreated in session 1 (S1), were randomized to one of four classes of glaucoma drops for S2 and had a prostaglandin analogue add-on for S3. Main Outcome Measures: Changes in IOP-related patterns were defined using (i) slopes from wake/sitting to sleep/supine; (ii) cosinor rhythmometry modelling; and (iii) area under receiver operating curve (AUC) of sleep period. Results: Mean patient age was 63.8±11.8 years. Positive linear slopes were seen from wake/sitting to sleep/supine at S1 (17.1±14.2mVeq/h) and S2 (5.5±23.9mVeq/h) and negative slopes at S3 (-1.9±29.4mVeq/h) (S1-S2, P=0.01; S1-S3, P=0.02). In the prostaglandin group, slopes changed significantly with introduction of drops (S1-S2, P<0.024), whereas they did not in a mixed group combining the three other classes (S1-S2, P=0.060). Overall, cosinor amplitudes were 98.4±46.5mVeq (S1), 113.0±35.6mVeq (S2) and 109.6±58.3mVeq (S3) (S1-S2, P=0.23; S1-S3, P=0.66; S2-S3, P=0.93). AUC were 91.8±63.0mVeq (S1), 76.3±102.7mVeq (S2) and 19.9±135.8mVeq (S3). Differences between sessions were not statistically significant (S1-S2, P=0.541; S1-S3, P=0.083; S2-S3, P=0.092). Conclusions: Prostaglandin analogues, but not other medications, seem to flatten the IOP-related increase at transition of the wake/sitting to the sleep/supine period, but do not seem to have an effect on acrophase and amplitude.