Introduction and objective Children admitted to the pediatric intensive care unit after cardiovascular surgery usually require treatment with antibiotics due to suspicion of infection. The aim of this study was to assess the effectiveness of procalcitonin in decreasing the duration of antibiotic treatment in children after cardiovascular surgery. Methods Prospective, interventional study carried out in a pediatric intensive care unit. Included patients under 18 years old admitted after cardiopulmonary bypass. Two groups were compared, depending on the implementation of the PCT-guided protocol to stop or de-escalate the antibiotic treatment (Group 1, 2011–2013 and group 2, 2014–2018). This new protocol was based on the decrease of the PCT value by 20% or 50% with respect to the maximum value of PCT. Primary endpoints were mortality, stewardship indication, duration of antibiotic treatment, and antibiotic-free days. Results 886 patients were recruited. There were 226 suspicions of infection (25.5%), and they were confirmed in 38 cases (16.8%). The global rate of infections was 4.3%. 102 patients received broad-spectrum antibiotic (4.7±1.7 days in group 1, 3.9±1 days in group 2 with p = 0.160). The rate of de-escalation was higher in group 2 (30/62, 48.4%) than in group 1 (24/ 92, 26.1%) with p = 0.004. A reduction of 1.1 days of antibiotic treatment (group 1, 7.7±2.2 and group 2, 6.7±2.2, with p = 0.005) and 2 more antibiotic free-days free in PICU in group 2 were observed (p = 0.001), without adverse outcomes. Conclusions Procalcitonin-guided protocol for stewardship after cardiac surgery seems to be safe and useful to decrease the antibiotic exposure. This protocol could help to reduce the duration of broad-spectrum antibiotics and the duration of antibiotics in total, without developing complications or adverse effects.