Objectives In hospitalized patients with skin and soft tissue infections (SSTIs), intravenous (IV) empiric antibiotic treatment is initiated. The best time point for switching from IV to oral treatment is unknown. We used an algorithm-based decision tree for the switch from IV to oral antibiotics within 48 hours and aimed to investigate the treatment outcome of this concept. Methods In a non-randomized trial, we prospectively enrolled 128 patients hospitalized with SSTI from July 2019 to May 2021 at three institutions. Clinical and biochemical response data during the first week and at follow-up after 30 days were analyzed. Patients fulfilling criteria for the switch from IV to oral antibiotics were assigned to the intervention group. The primary outcome was a composite definition consisting of the proportion of patients with clinical failure or death of any cause. Results Ninety-seven (75.8%) patients were assigned to the intervention group. All of them showed signs of clinical improvement (i.e.; absence of fever or reduction of pain) within 48 hours IV treatment, irrespective of erythema finding or biochemical response. The median total antibiotic treatment duration was 11 (IQR 9–;13) days in the invention and 15 (IQR 11-24) days in the non-intervention group (p<0.001). The median duration of hospitalization was 5 (IQR 4-6) days in the intervention group and 8 (IQR 6-12) days in the non-intervention group (p<0.001). There were five (5.2%) failures in the intervention group and one (3.2%) in the non-intervention group after a median follow-up of 37 days. Conclusions In this pilot trial, the proposed decision-algorithm for early switch from IV to oral antibiotics for SSTI treatment was successful in 95% of cases.