Background: Influenza A virus (flu-A) can cause lethal respiratory tract infections, as observed in a pandemic H1N1 outbreak in 2009. Vaccination using inactivated virus is advised to prevent severe flu-A infections with questionable efficacy. Recombinant hemagglutinin proteins (rHA) may prove to be an effective way of inducing protective immunity against flu-A infection. Dendritic cells and natural killer cells are players of innate immunity and play an important role in developing subsequent adaptive immunity against flu-A. Methods: We compare the effect of the whole flu-A virus and the rHAs from two different H1N1 virus (A/WSN/33,/Texas/05/2009) on the maturation and activation of human monocyte-derived dendritic cells (MoDCs) and beads-purified natural killer (NK) cells. Results:(i) rHA of flu-A induced maturation and activation of MoDCs as effective as whole Influenza A/WSN/33 virus, as demonstrated by increased CD80,CD83, CD86 expression; (ii) rHA induce lesser degree of apoptosis of DCs, compared to the whole influenza A/WSN/33 virus ( P < 0.05); (iii) rHA treated DC produced less cytokines (TNF-a , INF-a ) than did flu-A infected DCs (P<0.01). As to NKcells, we established that (i) Both flu-A and rHA resulted in apoptosis of NK cells; (ii) flu-A but not rHA induced down-regulation of NKp46 expression on NK cells; (iii) Natural killer cytotocixity was suppressed by flu-A (P<0.05) but not rHAs.(P>0.05).Conclusion(s):Taken together, rHA andflu-A showed differential effect on maturation and activation of human dendritic cells and NK cells. These findings may provide useful information for the development of more effective influenza vaccines.