Pericardial effusion (PE) after pediatric cardiac surgery is common. Because of the lack of a uniform classification of the presence and severity of PE, we evaluated PE altering clinical management: clinically relevant PE. Risk factors for clinically relevant PE were studied. After cardiac surgery, children were followed until 1 month after surgery. Preoperative variables were studied in the complete cohort. Perioperative and postoperative variables were studied in a case–control manner. Patients with and without clinically relevant PE were matched on age, gender, and diagnosis severity in a 1:1 ratio. Multivariate analysis was conducted using important preoperative variables from the complete cohort combined with perioperative and postoperative variables from the case–control data. 1241 surgical episodes in 1031 patients were included. Clinically relevant PE developed in 136 episodes (11.0%). Multivariate correlation with the outcome was present for age, BSA (adjusted odds ratio: 1.6, 95% CI 0.9–2.8), right-sided heart defect (adjusted odds ratio: 1.3, 95% CI 0.9–1.9), history of previous operation (adjusted odds ratio: 0.5, 95% CI 0.3–0.7), cardiopulmonary bypass use (adjusted odds ratio: 2.1, 95% CI 0.9–4.5), duration of CPAP postoperatively, and an inotropic score (adjusted odds ratio: 1.01, 95% CI 0.998–1.03). In this large patient cohort, 11.0% of postoperative periods of pediatric cardiac surgery were complicated by PE requiring alteration of treatment. Secondly, we newly identified cardiopulmonary bypass use and right-sided heart defects as risk factors for clinically relevant PE and confirmed previously described risk factors: age, CPAP duration, BSA, and inotropic score and a previously described risk reductor: history of previous operation.Electronic supplementary materialThe online version of this article (10.1007/s00246-018-2031-4) contains supplementary material, which is available to authorized users.