The Coronavirus disease 2019 (COVID-19) pandemic has significantly affected older adults. Identifying host COVID-19 susceptibility genes in elderly populations remains a challenge. Here, we aimed to identify host genetic factors influencing susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We genotyped 12 single nucleotide polymorphisms (SNPs) previously associated with the innate immune response in a total of 97 elderly (age >65 years) residents of three long-term care facilities located in the area of Barcelona, Spain. Individuals were PCR-tested during SARS-CoV-2 outbreaks between September and November 2020. SARS-CoV-2 PCR tests revealed infection in 81 residents. Importantly, the 16 uninfected residents remained SARS-CoV-2 seronegative until vaccination (January and February 2021). After adjusting for sex and age, we found that two SNPs were significantly associated with SARS-CoV-2 infection susceptibility: MMS19 nucleotide excision repair protein homolog (MMS19)/rs2236575 (p = 0.029) and interferon-induced helicase C domain-containing 1 (IFIH1)/rs1990760 (p = 0.034). No association with SARS-CoV-2 infection was found for the 10 additional genotyped SNPs, which included 4 SNPs on chromosome 12 in the gene encoding oligoadenylate synthetase (OAS). Our results indicate that MMS19 and IFIH1 genetic variants were associated with resistance to SARS-CoV-2 infection in a cohort of institutionalized seniors.