To comprehensively determine the associations between systemic medications and surgically treated cataract in the US population. Retrospective cross-sectional study. Participants aged ≥40 years from the 1999-2008 National Health andNutritionExamination Survey (NHANES) were included. Surgically treated cataract was defined as cataract requiring a procedure. Data on prescription drug use over the past 30 days were collected via home interviews. Drug categories for ophthalmic indications and those prescribed in less than 0.5% of the participants were excluded from the analysis. Separate logistic regression models were used to explore associations between each drug category and surgically treated cataract. The Benjamin-Hochberg procedure was used to control the false discovery rate. A total of 14,931 were included in the present analysis. The weighted prevalence of surgically treated cataract was 9.6% (n=2010). We identified 20 drug categories that had significant associations with surgically treated cataract, of which 8 associations remained statistically significant after further adjustment for pertinent comorbidities. The 3 drug categories with the highest odds ratio (OR) values were tricyclic antidepressants (OR, 2.21; 95% CI, 1.38-3.51; P=.001), insulin (OR, 2.13; 95% CI, 1.48-3.07; P=9.41×10-5) and group III antiarrhythmic agents (OR, 2.00; 95% CI, 1.25-3.19; P=.004). The use of sex hormone combinations among women reduced the risk of having surgically treated cataract (OR, 0.011; 95% CI, 0.001-0.089; P=5.98×10-5). Dose-response relationships were observed for all 8 drug categories. Our comprehensive evaluation provides new knowledge on the complex relationships between systemic medications and surgically treated cataract.