Studies during and immediately post-cardiopulmonary bypass (CPB) surgery have revealed that neutrophils (PMNs) are pivotal to post-CPB inflammation and innate immunity. The aim of this study was to investigate the effects of CPB on the PMN phenotype and respiratory burst function over a longer post-CPB period (up to day 5). Blood samples were collected pre-CPB and on days 1, 3, and 5 post-CPB from 20 patients. Changes to PMN surface expression of CD16, CD62L, CD11b, CD18, and CD43, and PMN respiratory burst activity were measured, together with the white blood cell count and absolute PMN count. Cardiopulmonary bypass induced neutrophilia on days 1 and 3. One day post-CPB, CD16 expression reached a nadir (P = 0.001), and platelet-activating factor-induced CD18 increase was depressed (P < 0.05). Three days post-CPB, CD43 expression peaked (P < 0.05), with a concomitant resistance to N-formyl-Met-Leu-Phe-induced CD11b upregulation (P < 0.05). The PMN respiratory burst activity declined continuously post-CPB until day 5. Neutrophilia on days 1 and 3 was associated with changes to surface molecules expression that may reduce PMN activation response. This study demonstrated that CPB depresses the respiratory burst activity of host PMNs for an extraordinarily longer period of at least 5 days even after neutrophilia had resolved. Collectively, the changes portray an autoprotective yet responsive homeostatic balance.