To examine the role of systemic medication on the risk of pseudophakic cystoid macular edema (PCME) following uneventful cataract surgery. A total of 269 eyes undergoing routine cataract surgery. Spectral-domain optical coherence tomography imaging was conducted before surgery and at 28days. Information about medication of the participants was gathered from The National Archive of Health Information (Kanta), an electronic pharmaceutical database. Systemic medication with angiotensin converting enzyme inhibitor/angiotensin II receptor antagonists (p<0.001), beta-blockers (β-blockers) (p=0.002), calcium channel blockers (CCBs) (p<0.001), nitrates (p=0.021) and lipophilic HMG-CoA reductase inhibitors (statins) (p<0.001) were more frequently prescribed to diabetic compared with nondiabetic patients. In eyes with steroid monotherapy (N=135), concomitant systemic medication with β-blockers (12.9±24.0μm versus 28.6±59.5μm, p=0.045), CCBs (12.0±22.1μm versus 26.3±55.6μm, p=0.041) and statins (12.9±22.8μm versus 30.0±61.9μm, p=0.038) attenuated a change in central retinal thickness (CRT) when compared to patients not receiving medication. In multivariable analysis, the use of CCBs remained as an independent protective factor against macular swelling at 28days (-0.23; 95% CI [-0.43 to -0.04]; p=0.021), when all systemic medications showing statistical significance were included (i.e. β-blockers, CCBs and statins) together with diabetes status. In eyes with nonsteroidal anti-inflammatory drug (NSAID) monotherapy (N=67) and steroid and NSAID combination therapy (N=67), CRT increase was moderate both with and without use of systemic medications. Systemic vasoactive medication may be protective against CRT change induced by cataract surgery in eyes at risk of PCME such as those with postoperative steroid monotherapy.