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Frontline health care workers (HCWs) have been particularly exposed to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) since the start of the pandemic but the clinical features and immune responses of those infected with SARS-CoV-2 have not been well described. In a prospective single center cohort study, we enrolled 196 frontline HCWs exposed to the SARS-Cov-2 and 60 patients with moderate and severe forms of the coronavirus disease 2019 (COVID-19). Serological tests and cytokines assay were performed to analyze SARS-CoV-2-specific humoral and cellular immunity. Of the 196 HCWs tested, 15% had specific antibodies against SARS-CoV-2 and 45% of seropositive HCWs were strictly asymptomatic. However, in comparison to moderate and severe forms, HCWs with mild or asymptomatic forms of COVID-19 showed lower specific IgA and IgG peaks, consistent with their mild symptoms, and a robust immune cellular response, illustrated by a high production of type I and II interferons. Further studies are needed to evaluate whether this interferon functional immune assay, routinely applicable, can be useful in predicting the risk of severe forms of COVID-19.