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AbstractObjective:We hypothesized that healthcare workers (HCWs) with high-risk exposures outside the healthcare system would have less asymptomatic coronavirus 2019 (COVID-19) disease and more symptoms than those without such exposures.Design:A longitudinal point prevalence study was conducted during August 17–September 4, 2020 (period 1) and during December 2–23, 2020 (period 2).Setting:Community based teaching health system.Participants:All HCWs were invited to participate. Among HCWs who acquired COVID-19, logistic regression models were used to evaluate the adjusted odds of asymptomatic disease using high-risk exposure outside the healthcare system as the explanatory variable. The number of symptoms between exposure groups was evaluated with the Wilcoxon rank-sum test. The risk of seropositivity among all HCS by work exposure was evaluated during both periods.Interventions:Survey and serological testing.Result:Seroprevalence increased from 1.9% (95% confidence interval [CI], 1.2%–2.6%) to 13.7% (95% CI, 11.9%–15.5%) during the study. Only during period 2 did HCWs with the highest work exposure (versus low exposure) have an increased risk of seropositivity (risk difference [RD], 7%; 95% CI, 1%–13%). Participants who had a high-risk exposure outside of work (compared to those without) had a decreased probability of asymptomatic disease (odds ratio [OR], 0.38; 95% CI, 0.16–0.86) and demonstrated more symptoms (median 3 [IQR, 2–6] vs 1 [IQR, 0–4]; P= .001).Conclusions:Healthcare-acquired COVID-19 increases the probability of asymptomatic or mild COVID-19 disease compared to community-acquired disease. This finding suggests that infection prevention strategies (including masks and eye protection) may be mitigating inoculum and supports the variolation theory in COVID-19.