ABSTRACT With the emergence of highly transmissible variants of concern, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still poses a global threat of coronavirus disease 2019 (COVID-19) resurgence. Cellular responses to novel variants are more robustly maintained than humoral responses, and therefore, cellular responses are of interest in assessing immune protection against severe disease in the population. We aimed to assess cellular responses to SARS-CoV-2 at the population level. IFNγ (interferon γ) responses to wild-type SARS-CoV-2 were analyzed using an ELISpot assay in vaccine-naive individuals with different humoral responses: Ig (IgM and/or IgG) seronegative (n = 90) and seropositive (n = 181) with low (<300 U/mL) or high (≥300 U/mL) humoral responses to the spike receptor binding domain (anti-S-RBD). Among the seropositive participants, 71.3% (129/181) were IFNγ ELISpot positive, compared to 15.6% (14/90) among the seronegative participants. Common COVID-19 symptoms such as fever and ageusia were associated with IFNγ ELISpot positivity in seropositive participants, whereas no participant characteristics were associated with IFNγ ELISpot positivity in seronegative participants. Fever and/or dyspnea and anti-S-RBD levels were associated with higher IFNγ responses. Symptoms of more severe disease and higher anti-S-RBD responses were associated with higher IFNγ responses. A significant proportion (15.6%) of seronegative participants had a positive IFNγ ELISpot. Assessment of cellular responses may improve estimates of the immune response to SARS-CoV-2 in the general population.IMPORTANCEData on adaptive cellular immunity are of interest to define immune protection against severe acute respiratory syndrome coronavirus 2 in a population, which is important for decision-making on booster-vaccination strategies. This study provides data on associations between participant characteristics and cellular immune responses in vaccine-naive individuals with different humoral responses.