Purpose: To investigate the association between early lifetime substance use on the development of severe visual acuity impairment or blindness on a national level. Methods: National Survey of Drug Use and Health data was used to identify cases of substance use before 21* years of age, within the past year, and cases of self-reported blindness or visual impairment. Univariable and multivariable binary logistic regression with time-dependency was performed to evaluate odds of visual impairment influenced by 16 substances separated into three classes: prescription, non-prescription, and illicit drugs. Adjusted variables of interest included gender, marital status, race, level of education, total family income, poverty level, population density, and history of chronic disease. Results: 55,824 total responses were analyzed with 2577 (4.6%) cases of self-reported blindness or significant visual impairment. All early-use substance categories, including prescription, non-prescription, and illegal substances, were significantly associated with self-reported VI (OR 2.068, CI 1.451– 2.949, p< 0.001; OR 1.352, CI 1.227– 1.489, p< 0.001); OR 1.211, CI 1.086– 1.352, p< 0.001), respectively). Non-prescription substances displayed parallel significances amongst all constituents (alcohol, cigarettes, inhalants, and marijuana) (OR=1.227, CI 1.12– 1.344, p< 0.001; OR 1.363, CI 1.243– 1.495, p< 0.001; OR 1.418, CI 1.134– 1.774; OR 1.388, CI 1.27– 1.518, p< 0.001, respectively). Univariable and multivariable analysis revealed several significant demographical and clinical adjustors. Conclusion: Early lifetime use of all three classes of substances is associated with enhanced odds of subsequent visual impairment or blindness. Several readily available and commonly used substances have a greater risk. These findings may help clinicians and public health agencies in mitigation ventures including education, prevention, and rehabilitation efforts. [ABSTRACT FROM AUTHOR]