Pleural effusion appears in approximately 40% of patients with pneumonia. Given that microbiology results are often negative, its diagnosis is frequently based on clinical criteria. Our study consisted of 266 patients, divided into infectious (n = 34), tuberculous (n = 54), paraneoplastic (n = 63), miscellaneous exudates (n = 53), and transudates (n = 62). Interleukin (IL)-6, IL-8, and IL-1beta were measured in the pleural fluid and serum of all patients, as well as the different cell populations in the pleural fluid. Analysis of the receiver operating characteristic curves of the different ILs in pleural fluid for the diagnosis of parapneumonic/empyematous effusion showed IL-6 with a sensitivity of 38.2% and specificity of 97.4%, IL-8 with a sensitivity of 73.5% and specificity of 65.1%, IL-1beta with a sensitivity of 55.6% and specificity of 91.3%, and total neutrophil count in pleural fluid (PNEU) with a sensitivity of 62.9% and specificity of 91.1%. The combination of IL-1beta and PNEU improved the yield, with a sensitivity of 75.7% and a specificity of 83.1%.