Abstract Background A better understanding of reinfection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become one of the healthcare priorities in the current pandemic. We determined the rate of reinfection, associated factors, and mortality during follow-up in a cohort of patients with SARS-CoV-2 infection. Methods We analyzed 9119 patients with SARS-CoV-2 infection who received serial tests in total of 62 healthcare facilities in the United States between 1 December 2019 and 13 November 2020. Reinfection was defined by 2 positive tests separated by interval of >90 days and resolution of first infection was confirmed by 2 or more consecutive negative tests. We performed logistic regression analysis to identify demographic and clinical characteristics associated with reinfection. Results Reinfection was identified in 0.7% (n = 63, 95% confidence interval [CI]: .5%–.9%) during follow-up of 9119 patients with SARS-CoV-2 infection. The mean period (±standard deviation [SD]) between 2 positive tests was 116 ± 21 days. A logistic regression analysis identified that asthma (odds ratio [OR] 1.9, 95% CI: 1.1–3.2) and nicotine dependence/tobacco use (OR 2.7, 95% CI: 1.6–4.5) were associated with reinfection. There was a significantly lower rate of pneumonia, heart failure, and acute kidney injury observed with reinfection compared with primary infection among the 63 patients with reinfection There were 2 deaths (3.2%) associated with reinfection. Conclusions We identified a low rate of reinfection confirmed by laboratory tests in a large cohort of patients with SARS-CoV-2 infection. Although reinfection appeared to be milder than primary infection, there was associated mortality.