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Introduction COVID-19 continues to impact vulnerable populations disproportionally. Identifying modifiable risk factors could lead to targeted interventions to reduce infections. The purpose of this study is to identify risk factors for testing positive for SARS-CoV-2. Methods Using electronic health records collected from a large ambulatory care system in northern and central California, the study identified patients who had a test for SARS-CoV-2 between 2/20/2020 and 3/31/2021. The adjusted effect of active and passive smoking and other risk factors on the probability of testing positive for SARS-CoV-2 were estimated using multivariable logistic regression. Analyses were conducted in 2021. Results Of 556 690 eligible patients in our sample, 70 564 (12.7%) patients tested positive for SARS-CoV-2. Younger age, being male, racial/ethnic minorities, and having mild major comorbidities were significantly associated with a positive SARS-CoV-2 test. Current smokers (adjusted OR: 0.69, 95% CI: 0.66-0.73) and former smokers (adjusted OR: 0.92, 95% CI: 0.89-0.95) were less likely than nonsmokers to be lab-confirmed positive, but no statistically significant differences were found when comparing passive smokers with non-smokers. The patients with missing smoking status (25.7%) were more likely to be members of vulnerable populations with major comorbidities (adjusted OR ranges from severe: 2.52, 95% CI = 2.36-2.69 to mild: 3.28, 95% CI = 3.09-3.48), lower income (adjusted OR: 0.85, 95% CI: 0.85-0.86), aged 80 years or older (adjusted OR: 1.11, 95% CI: 1.07-1.16), have less access to primary care (adjusted OR: 0.07, 95% CI: 0.07-0.07), and identify as racial ethnic minorities (adjusted OR ranges from Hispanic: 1.61, 95% CI = 1.56-1.65 to Non-Hispanic Black: 2.60, 95% CI = 2.5-2.69). Conclusions Our findings suggest that the odds of testing positive for SARS-CoV-2 were significantly lower in smokers compared to nonsmokers. Other risk factors include missing data on smoking status, being under 18, being male, being a racial/ethnic minority, and having mild major comorbidities. Since those with missing data on smoking status were more likely to be members of vulnerable populations with higher smoking rates, the risk of testing positive for SARS-CoV-2 among smokers may have been underestimated due to missing data on smoking status. Future studies should investigate the risk of severe outcomes among active and passive smokers, the role that exposure to tobacco smoke constitutes among nonsmokers, the role of comorbidities in COVID-19 disease course, and health disparities experienced by disadvantaged groups.