Therapeutic thoracentesis is highly effective in providing symptomatic improvement in patients with large volume pleural effusion (PE). However, some physiological effects of pleural fluid (PF) withdrawal are still not fully elucidated. The study aimed to evaluate alterations in the breathing pattern, pulmonary function, and arterial blood gases (ABG) in relation to both withdrawn PF volume and pleural pressure (Ppl) changes in patients undergoing therapeutic thoracentesis. This prospective, observational, cross‑sectional study included 37 patients with large volume PE. Respiratory rate (RR), dyspnea, pulmonary function, and ABG were assessed before the thoracentesis, at the termination of the PF withdrawal and 1, 3, and 24 hours after the procedure. The volume of PF drained, Ppl, and tidal volume (TV) were monitored during the thoracentesis. Thoracentesis resulted in a transient but significant increase in RR directly after the procedure, and a transient decrease, followed by subsequent increase in TV. There was a significant and constant increase in forced vital capacity up to 24 hours after thoracentesis (P = 0.001). Oxygen partial pressure (PaO2) significantly improved directly after PF withdrawal (P = 0.01) and returned to baseline values after 24 hours. Thoracentesis was invariably associated with a significant increase in the amplitude of Ppl (Ppl_ampl) changes during the respiratory cycle (P <0.001). Therapeutic thoracentesis results in a modest improvement in pulmonary function, tran-sient increase in PaO2 and increase in Ppl_ampl. The improvement in pulmonary function and ABG is closely related to the volume of PF drained and pleural elastance. The increase in Ppl_ampl probably represents a more efficient work of the respiratory muscles.