Importance: There is limited understanding of the associations between systemic medication use and intraocular pressure (IOP) in the general population. Objective: To examine the association between systemic medication use and IOP in a multiethnic Asian population. Design, Setting, and Participants: In this post hoc analysis of the Singapore Epidemiology of Eye Diseases study, a population-based study of 10 033 participants (78.7% response rate) from 3 racial/ethnic groups (Chinese [recruited from February 9, 2009, through December 19, 2011], Malays [recruited from August 16, 2004, though July 10, 2006], and Indians [recruited from May 21, 2007, through December 29, 2009]), participants with glaucoma, previous ocular surgery, or trauma and an IOP asymmetry greater than 5 mm Hg between eyes were excluded. Intraocular pressure was measured using Goldmann applanation tonometry. An interviewer-administered questionnaire was conducted to collect data on medication and other variables. Data analysis was performed from August 1 through October 31, 2015. Main Outcomes and Measures: Associations between medication and IOP were assessed using linear regression models adjusted for age, sex, body mass index, ethnicity, and the medical condition for which the medication was taken (angiotensin-converting enzyme inhibitors [ACEIs], angiotensin receptor blockers [ARBs], and β-blockers adjusted for blood pressure, statins adjusted for lipids, and biguanides, sulfonylureas, α-glycosidase inhibitors [AGIs], and insulin adjusted for glycosylated hemoglobin). Medications associated with significant IOP differences were incorporated into regression models adjusted for concomitant use of multiple medications. Generalized estimating equation models were used to account for correlation between eyes. Results: Of the 10 033 participants, we analyzed 8063 (mean [SD] age, 57.0 [9.6] years; 4107 female [50.9%]; 2680 Chinese [33.2%], 2757 Malay [34.2%], and 2626 Indian [32.6%] individuals). Systemic β-blocker use was independently associated with an IOP of 0.45 mm Hg lower (95% CI, -0.65 to -0.25 mm Hg; P < .001). Conversely, higher mean IOP was associated with use of ACEIs (0.33 mm Hg higher; 95% CI, 0.08 to 0.57 mm Hg; P = .008), ARBs (0.40 mm Hg higher; 95% CI, 0.40-0.75 mm Hg; P = .02), statins (0.21 mm Hg higher; 95% CI, 0.02-0.4 mm Hg; P = .03), and sulfonylureas (0.34 mm Hg higher; 95% CI, 0.05-0.63 mm Hg; P = .02). An interaction between medication classes for additive, synergistic, or antagonistic effects on IOP was not identified. Conclusions and Relevance: Although systemic β-blocker use was associated with lower IOP and systemic ACEI, ARB, statin, and sulfonylurea use was associated with higher IOP in this study, the associations were modest at best. Only the associations with systemic hypoglycemic agents were greater than 1 mm Hg, a threshold that has translated to a 14% greater risk of incident glaucoma across 5 years in other studies. At this point, the effect of systemic medication on IOP in eyes with glaucoma is not well elucidated but important. Our findings indicate that patients with glaucoma may potentially be at risk of higher or lower IOP, depending on medication class, and this would in turn affect management of IOP control.