Objectives: Miniaturized cardiopulmonary bypass (MCPB) is increasingly used in cardiac surgery, because it can lower clinically significant complications such as systemic inflammatory response, haemolysis and high transfusion requirements. A limitation of MCPB is the risk of excessive negative pressure in the venous line during volume depletion, probably leading to gaseous microembolism. Methods: In an experimental study with 24 pigs, we compared conventional open cardiopulmonary bypass (CCPB group, n = 11) with MCPB (n = 13). The same pump and identical tubing materials were used in both groups. Primary endpoints were pressure values in the venous line and the right atrium as well as the amount of air bubbles >500 μm. Secondary endpoints were biochemical parameters of systemic inflammatory response, ischaemia, haemodilution and haemolysis. Results: Nearly 20% of venous pressure values were below -150 mmHg and approximately 10% of the right atrial pressure values were below -100 mmHg in the MCPB group, during the experiment. No such low values were observed in the CCPB group. In addition, the number of large arterial air bubbles was higher in the MCPB group compared with the CCPB group (mean ± standard deviation [SD]: 13 444 ± 5709 vs 0.9 ± 0.6, respectively; P < 0.001). Bubble volume was also significantly larger during MCPB compared with CCPB (mean ± SD: 1522 ± 654 vs 4.1 ± 2.5 μl, respectively; P < 0.001). Blood levels of interleukin-6, free haemoglobin and creatine kinase were significantly higher in the CCPB group compared with the MCPB group. Conclusions: Despite the benefits of MCPB regarding systemic inflammatory response and haemolysis, this technique is associated with excessive negative venous line pressures and a significant increase in the number and volume of arterial air bubbles compared with CCPB. Mini-perfusion systems and the management of MCPB require further refinements to avoid such adverse effects.