Background Chemical fibrinolysis has been shown to be as effective as surgical debridement for the treatment of pediatric empyema. However, no studies effectively evaluate antibiotic treatment. We evaluated antibiotic utilization among different treatments of pediatric empyema. Methods This is a retrospective review of 169 empyema patients who underwent chemical and/or mechanical fibrinolysis at a dedicated children's hospital from 2005-2013. Data points included duration of therapy, cultures, presence of necrosis or abscess, and adverse drug reactions. Immunocompromised patients and those with additional foci of infection were excluded. Results Twenty-seven patients underwent video-assisted thoracoscopic surgery (VATS), 123 had chemical fibrinolysis via tube thoracostomy with tissue plasminogen activator (tPA), and 19 had tPA followed by VATS. The mean (±standard deviation) duration of total antibiotic therapy was 25.7 ± 6.5 d; following a 24 h afebrile period of 19.4 ± 6.3 d. Patients who had tPA had a significantly shorter duration of parenteral antibiotic therapy when compared with primary VATS (9.2 ± 3.6 d versus 11.6 ± 5.5 d, P = 0.04) and VATS following tPA (9.2 ± 3.6 d versus 14.3 ± 8.1 d, P < 0.01). Patients with necrosis or abscess (n = 26) had an increased total duration of antibiotics (29.3 ± 5.7 d versus 25.1 ± 6.4 d, P < 0.01). Seventy patients (41%) had an adverse reaction related to antibiotic use. Conclusions Patients with empyema currently receive a protracted variable course of antibiotic therapy influenced by primary treatment and the presence of necrosis or abscess. With a high incidence of adverse reactions, a standardized protocol with truncated treatment duration should be considered.