The impact of pre-existing common cold coronavirus (CCCoV) antibodies (Abs) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and pathogenesis remains poorly defined. We evaluated these associations in a cohort of hospitalized patients with COVID-19 and respiratory failure of varying severity. Patients with respiratory failure from other causes (non-COVID-19) were evaluated as controls. We demonstrated a positive correlation between levels of CCCoV and SARS-CoV-2 Abs using CCCoV and SARS-CoV-2 N and S protein peptide-specific ELISA. Consistent with the above, moderately increased levels of CCCoV-specific Abs in non-COVID-19 vs. COVID-19 patients suggest potential protective effects. Further, higher SARS-CoV-2 N protein-specific and CCCoV Ab levels were observed among surviving vs. non-surviving COVID-19 positive patients. However, the highest SARS-CoV-2 N and S protein-specific IgG and IgA Ab levels were noted in the patients with the most severe clinical disease. Finally, advanced age, cancer and immunosuppression were associated with significantly higher mortality and reduced SARS-CoV-2 and CCCoV Ab levels. Thus, our data highlight that sufficient SARS-CoV-2 N protein-specific Ab responses improve clinical outcomes in severely ill COVID-19 patients. We also confirmed that pre-existing CCCoV-specific Abs do not inhibit the SARS-CoV-2 Ab response and may further reduce the prevalence and/or severity of COVID-19.