The mouse-adapted A/PR/8/34 (PR8; H1N1) virus infects airway macrophages poorly and is virulent in mice. Herein, we have investigated factors contributing to the ability of PR8 to evade murine macrophages. We demonstrate that the hemagglutinin of PR8 binds preferentially to alpha(2,3)-linked sialic acid (SA) and that murine macrophages express alpha(2,6)-linked SA. Moreover, resialylation of macrophages to express alpha(2,3)-linked SA restored susceptibility to PR8. Thus, during adaptation of human influenza viruses to growth in mice, a switch in receptor specificity from alpha(2,6)-linked SA to alpha(2,3)-linked SA is likely to favour evasion of attachment, entry and destruction by airway macrophages.