Objectives: We aimed to evaluate the impact of respiratory symptoms and positive viral testing on the risk of serious bacterial infections (SBIs). Methods: A retrospective study was conducted that included infants (0–60 days) presenting with a fever between 2001 and 2022 at a tertiary hospital in northern Israel. Demographic, clinical, and laboratory parameters were collected, and risk factors for SBIs were analyzed. Results: Data from a total of 3106 infants, including data from blood, urine, and CSF cultures, were obtained in 96.6%, 89%, and 29% of cases, respectively. A fever without respiratory symptoms (fever only) was present in 1312 infants, while 1794 had a fever and respiratory symptoms—427 were positive for a respiratory virus (virus+), 759 tested negative (virus−), and 608 were not tested. The SBI rate was 5.1% vs. 7.5% in the fever-and-respiratory group vs. the fever-only group (p = 0.004, OR = 0.65 (95% CI = 0.49–0.88)) and 2.8% vs. 7% in the virus+ vs. virus− group (p = 0.002, OR = 0.385, (95% CI = 0.203–0.728)). The male gender, an age < 1 month, leukocytosis > 15 × 109/L, or a CRP > 2 mg/dL increased the risk of SBIs. Respiratory symptoms or a confirmed viral infection reduced the risk of SBIs in the presence of the above risk factors. Conclusions: Respiratory symptoms and a positive viral test decreased the risk of SBIs. Combining rapid viral testing with clinical variables may identify low-risk infants. Despite the relatively low risk of SBIs in individuals with viral infections, conducting prospective studies remains essential for accurately predicting the occurrence of these potentially life-threatening infections.