Background During pneumonia, normal alveolar areas coexist adjacently with consolidated areas, and high inspiratory efforts may predispose to lung damage. To date, no study has evaluated different degrees of effort during Biphasic positive airway pressure (BIVENT) on lung and diaphragm damage in experimental pneumonia, though largely used in clinical setting. We aimed to evaluate lung damage, genes associated with ventilator-induced lung injury (VILI) and diaphragmatic injury, and blood bacteria in pressure-support ventilation (PSV), BIVENT with low and high inspiratory efforts in experimental pneumonia. Material and methods Twenty-eight male Wistar rats (mean ± SD weight, 333±78g) were submitted Pseudomonas aeruginosa-induced pneumonia. After 24-h, animals were ventilated for 1h in: 1) PSV; 2) BIVENT with low (BIVENT_Low-Effort); and 3) BIVENT with high inspiratory effort (BIVENT_High-Effort). BIVENT was set at P_high to achieve V_T = 6 ml/kg and P_low at 5 cmH₂O (n = 7/group). High- and low-effort conditions were obtained through anaesthetic infusion modulation based on neuromuscular drive (P_0.1). Lung mechanics, histological damage score, blood bacteria, and expression of genes related to VILI in lung tissue, and inflammation in diaphragm tissue. Results Transpulmonary peak pressure and histological damage score were higher in BIVENT_High-Effort compared to BIVENT_Low-Effort and PSV [16.1 ± 1.9cmH₂O vs 12.8 ± 1.5cmH₂O and 12.5 ± 1.6cmH₂O, p = 0.015, and p = 0.010; median (interquartile range) 11 (9–13) vs 7 (6–9) and 7 (6–9), p = 0.021, and p = 0.029, respectively]. BIVENT_High-Effort increased interleukin-6 expression compared to BIVENT_Low-Effort (p = 0.035) as well as expressions of cytokine-induced neutrophil chemoattractant-1, amphiregulin, and type III procollagen compared to PSV (p = 0.001, p = 0.001, p = 0.004, respectively). Tumour necrosis factor-α expression in diaphragm tissue and blood bacteria were higher in BIVENT_High-Effort than BIVENT_Low-Effort (p = 0.002, p = 0.009, respectively). Conclusion BIVENT requires careful control of inspiratory effort to avoid lung and diaphragm damage, as well as blood bacteria. P_0.1 might be considered a helpful parameter to optimize inspiratory effort.