BACKGROUND Pneumoconiosis is a diffuse interstitial fibronodular lung disease, which is caused by the inhalation of crystalline silica. Whole lung lavage (WLL) is a therapeutic procedure used to treat pneumoconiosis. This study is to compare the effects of different negative pressure suction on lung injury in patients with pneumoconiosis undergoing WLL. METHODS A prospective study was conducted with 24 consecutively pneumoconiosis patients who underwent WLL from March 2020 to July 2020 at Emergency General Hospital, China. The patients were divided into two groups: high negative suction pressure group (group H, n = 13, negative suction pressure of 300-400 mmHg) and low negative suction pressure group (group L, n = 11, negative suction pressure of 40-50 mmHg). The arterial blood gas, lung function, lavage data, oxidative stress, and inflammatory responses to access lung injury were monitored. RESULTS Compared with those of group H, the right and left lung residual were significantly increased in the group L (P = 0.04, P = 0.01). Potential of hydrogen (pH), arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), lactic acid (LAC) and glucose (GLU) varied from point to point in time (P < 0.01, respectively). There was statistical difference in the trend of superoxide dismutase (SOD) and interleukin-10 (IL-10) over time between the two groups (P < 0.01, P = 0.02). In comparison with the group H, the levels of IL-10 (P = 0.01) and SOD (P < 0.01) in WLL fluid were significantly increased in the group L. There was no statistical difference in the trend of maximal volumtary ventilation (MVV), forced vital capacity (FVC), forced expiratory volume in one second (FEV1%), residual volume (RV), residual volume/total lung capacity (RV/TLC), carbon monoxide dispersion factor (DLCO%), forced expiratory volume in one second/ forced vital capacity (FEV1/FVC%) over time between the two groups (P > 0.05, respectively). CONCLUSIONS Low negative suction pressure has the potential benefit to reduce lung injury in patients with pneumoconiosis undergoing WLL, although it can lead to increased residual lavage fluid. Despite differing suction strategies, pulmonary function parameters including FEV1%, RV and DLCO% became worse than before WLL. Trial Registration Chinese Clinical Trial registration number ChiCTR2000031024, 21/03/2020.