Management for Shire Pharmaceuticals has unanimously rejected a £27bn ($46bn) informal bid from US drug giant AbbVie.
The London-listed drug firm rejected the takeover bid because it undervalued the group.
Shire said in a statement: "The board of Shire decided unanimously to reject the proposal on the basis that it fundamentally undervalued the company and its prospects."
AbbVie had earlier revealed a 4626-pence-per-share proposal.
Shire has no single controlling shareholder and has been seen as a likely takeover target for US drugmakers.
It specialises in the treatment of rare diseases business and has an attractive tax base, by being domiciled in Ireland.
Early London trading in Shire shares were up more than 13% after news of the AbbVie bid was announced, before climbing to 19% in mid-afternoon.
Shire said the offer denied shareholders full benefits of its future strategy.
The firm said it expected to more than double its 2013 annual product sales to £5.8bn ($10bn) by 2020 and told shareholders not to take action in relation to the takeover bid.
It also warned about concerns of the US firm shifting its tax domicile in the UK.
The concerns mirror those raised about the recent failed attempt by Pfizer to buy UK rival AstraZeneca.
Industry experts said they believed AbbVie would need to boost its offer to above £50-per-share for a deal to take place.
Jefferies analysts said in a briefing note: "We see limited product portfolio synergies, hence assume cost savings, tax benefits, diversification, and Shire's attractive growth to be the merger and acquisition drivers."
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