Background: The abuse of antibiotics during the SARS-CoV-2 pandemic might have disrupted efforts to curb the further development and spread of the antimicrobial resistance ofStaphylococcus aureusinfection andStaphylococcusspp. coagulase-negative (CoNS) agents of nosocomial bloodstream infections (NBSIs). The purpose of our work was to study the resistance patterns ofStaphylococcus aureusand CoNS through the analysis of blood cultures in hospitalized SARS-CoV-2-positive and SARS-CoV-2-negative patients (pts.). Materials and methods: During the period January 2018–June 2021, a retrospective case–control study was performed on blood cultures positive forStaphylococcusspp. detected in 177 adult pts. (≥18 years old) hospitalized for >48 hours at Sant’Elia Hospital, Caltanissetta. Results:Staphylococcus aureuswas isolated in 33.9% of blood culture samples, and among CoNS, the most frequent strains wereStaphylococcus capitis(18.6%) andStaphylococcus hominis(18.1%). Patients aged ≥ 65 years, with a greater number of males, comprised the SARS-CoV-2-negative pts. (71.8% vs. 52.2%,p= 0.0154). Among the SARS-CoV-2-positive patients, the significant resistance ofStaphylococcus aureuswas only observed for erythromycin (57.1%). The oxacillin resistance ofStaphylococcus capitiswas higher in SARS-CoV-2-positive than in negative pts. (90% and 78.3%, respectively). Comparing the two groups, we found an increase in resistance in SARS-CoV-2-negative patients for the following antibiotics: gentamicin forStaphylococcus aureus(p= 0.007), clindamycin and erythromycin (p= 0.012) forStaphylococcus hominisand oxacillin and rifampicin forStaphylococcus haemoliticus(p= 0.012). Conclusions: Our study confirms the relevance of oxacillin-resistantStaphylococcus aureusin being responsible for bloodstream infection and draws attention to highly oxacillin-resistant CoNS such asStaphylococcus capitis. The presence of resistant strains of CoNS in hospitals can be worrying, as it limits treatment options and worsens outcomes. The Infection Control Committee (ICC) recommends new treatment strategies to decrease colonization and infections. As part of the implementation of a bloodstream infection prevention program, the authors encourage the introduction of a report on the antimicrobial resistance of hospital bacteremia due to CoNS.