Background: Mechanical ventilation, especially large tidal volume (V-t) one-lung ventilation (OLV), can cause ventilator-induced lung injury (VILI) that can stimulate cytokines. Meanwhile, cytokines are considered very important factor influencing coronary heart disease (CHD) patient prognosis. So minimization of pulmonary inflammatory responses by reduction of cytokine levels for CHD undergoing lung resection during OLV should be a priority. Because previous studies have demonstrated that lung-protective ventilation (LPV) reduced lung inflammation, this ventilation approach was studied for CHD patients undergoing lung resection here to evaluate the effects of LPV on pulmonary inflammatory responses. Methods: This is a single center, randomized controlled trial. Primary endpoint of the study are plasma concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-10 and C-reactive protein (CRP). Secondary endpoints include respiratory variables and hemodynamic variables. 60 CHD patients undergoing video-assisted thoracoscopic lung resection were randomly divided into conventional ventilation group [10 mL/kg Vt and 0 cmH(2)O positive end-expiratory pressure (PEEP), C group] and protective ventilation group (6 mL/kg Vt and 6 cmH(2)O PEEP, P group; 30 patients/group). Hemodynamic variables, peak inspiratory pressure (Ppeak), dynamic compliance (Cdyn), arterial oxygen tension (PaO2) and arterial carbon dioxide tension (PaCO2) were recorded as test data at three time points: T1-endotracheal intubation for two-lung ventilation (TLV) when breathing and hemodynamics were stable; T2-after TLV was substituted with OLV when breathing and hemodynamics were stable; T3-OLV was substituted with TLV at the end of surgery when breathing and hemodynamics were stable. The concentrations of TNF-alpha, IL-6, IL-10 and CRP in patients' blood in both groups at the very beginning of OLV (beginning of OLV) and the end moment of the surgery (end of surgery) were measured. Results: The P group exhibited greater PaO2, higher Cdyn and lower Ppeak than the C group at T2, T3 (P<0.05). At the end moment of the surgery, although the P group tended to exhibit higher TNF-alpha and IL-10 values than the C group, the differences did not reach statistical significance(P=0.0817, P=0.0635). Compared with C group at the end moment of the surgery, IL-6 and CRP were lower in P group, the differences were statistically significant (P=0.0093, P=0.0005). There were no significant differences in hemodynamic variables between the two groups (P>0.05). Conclusions: LPV can effectively reduce the airway pressure, improve Cdyn and PaO2, reduce concentrations of IL-6 and CRP during lung resection of CHD patients.