Enhanced recovery after surgery protocols have shown improved clinical outcomes after lung resection surgery, but their application after empyema surgery is still limited. We retrospectively evaluated the outcomes of an adapted enhanced recovery after surgery (ERAS) protocol for immunocompromised patients who underwent video-assisted thoracoscopic surgery (VATS) surgery for chronic empyema between December 2013 and December 2021. The patients were divided into an ERAS group and a conventional treatment group. Peri-operative data were collected and compared between the two groups. The primary outcome was post-operative length of stay. Secondary outcomes were post-operative pain and post-operative complications (air leaks, atelectasis). A total of 86 patients, 45 in the ERAS group and 41 in the non-ERAS group, were considered. Chest tube duration (6.4 ± 2.3 vs. 13.6 ± 6.8 days) and post-operative length of stay (7.6 ± 1.6 vs. 16.9 ± 6.9 days) were significantly shorter in the ERAS group. The volume of chest drainage (103 ± 78 vs. 157 ± 89 mL/day) was significantly smaller in the ERAS group. There were no significant differences in operative time, blood loss, need for transfusion, tube reinsertion and median VAS score. The incidence of air leaks and atelectasis was significantly reduced in the ERAS group, as was the need for bronchoscopic aspiration. The application of an ERAS protocol after empyema VATS surgery for immunocompromised patients improved the surgical outcome, reducing the post-operative length of stay and rate of complications.