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High-risk smoking and exposure to isoniazid (INH) have been associated with increased risk of ototoxicity. The purpose of the study was to investigate whether high-risk smoking is associated with increased incidence of ototoxicity in patients treated with INH. A retrospective cohort study was performed using electronic medical record data from 2004 to 2016. Of the 103,345 INH-treated patients, 21,354 (21%) were smokers and 18,161 (18%) were obese. Using the CDC definitions for high-risk smoking, 5,185 (2.67%) were classified as high-risk smokers. High-risk smokers on INH were more likely to have a higher cumulative dose of INH and a higher cumulative dose of rifampin. High-risk smokers on INH were also more likely to develop rash (odds ratio [OR] = 1.93, 95% confidence interval [CI]: 1.77-2.11), sinusitis (OR = 1.93, 95% CI: 1.79-2.09), hepatitis B (OR = 1.24, 95% CI: 1.17-1.31), hepatotoxicity (OR = 2.47, 95% CI: 2.19-2.78), vertigo (OR = 1.95, 95% CI: 1.78-2.14) and perisinusitis (OR = 1.74, 95% CI: 1.58-1.93), as well as lower cumulative dose of INH (OR = 0.99, 95% CI: 0.99-1.00) and rifampin (OR = 0.97, 95% CI: 0.95-0.98). High-risk smoking has a higher incidence

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