Sialidase fusion protein is reported to have great potential to combat seasonal and pandemic influenza, because it may prevent influenza virus infection by removing all sialic acid receptors from host cells. Meanwhile, recent studies have demonstrated that absence of 2-6 sialic acid does not protect a cell from influenza infection, and influenza virus can infect desialylated cells, suggesting that accessible surface sialic acid is dispensable for influenza virus infection. In addition, studies using animal models have shown that neuraminidase promotes adherence and invasion of Streptococcus pneumoniae, because cleavage of sialic acid from host cells exposes cryptic receptors for S. pneumoniae. The purpose of this article is to comment on the benefits and potential risks of using sialidase fusion protein as an experimental drug to combat seasonal and pandemic influenza.