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COVID-19 is characterized by a wide range of clinical manifestations, where aging, underlying diseases, and genetic background are related to worse outcomes. In the present study, the differential expression of seven genes related to immunity, <i>IRF9</i>, <i>CCL5</i>, <i>IFI6</i>, <i>TGFB1</i>, <i>IL1B</i>, <i>OAS1</i>, and <i>TFRC</i>, was analyzed in individuals with COVID-19 diagnoses of different disease severities. Two-step RT-qPCR was performed to determine the relative gene expression in whole-blood samples from 160 individuals. The expression of <i>OAS1</i> (<i>p</i> < 0.05) and <i>IFI6</i> (<i>p</i> < 0.05) was higher in moderate hospitalized cases than in severe ones. Increased gene expression of <i>OAS1</i> (OR = 0.64, CI = 0.52–0.79; <i>p</i> = 0.001), <i>IRF9</i> (OR = 0.581, CI = 0.43–0.79; <i>p</i> = 0.001), and <i>IFI6</i> (OR = 0.544, CI = 0.39–0.69; <i>p</i> < 0.001) was associated with a lower risk of requiring IMV. Moreover, <i>TGFB1</i> (OR = 0.646, CI = 0.50–0.83; <i>p</i> = 0.001), <i>CCL5</i> (OR = 0.57, CI = 0.39–0.83; <i>p</i> = 0.003), <i>IRF9</i> (OR = 0.80, CI = 0.653–0.979; <i>p</i> = 0.03), and <i>IFI6</i> (OR = 0.827, CI = 0.69–0.991; <i>p</i> = 0.039) expression was associated with patient survival. In conclusion, the relevance of <i>OAS1</i>, <i>IRF9</i>, and <i>IFI6</i> in controlling the viral infection was confirmed.