It is known that cardiopulmonary bypass causes an inflammatory reaction with an associated morbidity and mortality. Several anti-inflammatory strategies have been implemented to reduce this response, including leukocyte removal from the circulation using specialised filters. The aim of this study is to systematically review the available evidence on leukocyte filtration in cardiac surgery, focusing on its effect on systemic inflammation and whether this has influenced clinical outcomes. Five electronic databases were systematically searched for studies reporting the effect of leukocyte filtration at any point within the cardiopulmonary bypass circuit in humans. Reference lists of all identified studies were checked for any missing publications. Two authors independently extracted the data from the included studies. Whilst systemic leukodepleting filters do not appear to consistently lower leukocyte counts, they may preferentially remove activated leukocytes. Small improvements in early post-operative lung function in patients receiving systemic leukodepletion have been reported, but this does not lead to reduced hospital stay or decreased mortality. There is substantial evidence that cardioplegic leukocyte filtration attenuates the reperfusion injury at a cellular level, but this has not been translated into clinical improvements. Finally, whilst various strategies involving multiple leukocyte filters, or the incorporation of pharmacological agents into leukocyte-depleting protocols have been evaluated, the current available results are not conclusive. Our study suggests that there is not enough high quality or consistent evidence to draw guidelines regarding the use of leukocyte-depleting filters within routine cardiac surgical practice.