The rejection came hours after Pfizer had lifted its informal cash and shares bid to the equivalent of 76 billion euros, as it seeks to strengthen its research in cancer and slash its tax bill.
The Viagra maker offered 50 pounds (USD 84, 61 euros) per AstraZeneca share, higher than the previous bid worth USD 99 billion.
"The financial and other terms described in the (new) proposal are inadequate, substantially undervalue AstraZeneca and are not a basis on which to engage with Pfizer," the British group said in a statement.
"It seems the main driver behind the deal is the desire of Pfizer to shelter USD 70 billion of its cash pile from US taxation rules, and that doesn't seem a sufficiently good reason to do a deal if you are AstraZeneca," said CMC chief strategist Michael Hewson.
He added: "The Pfizer CEO has talked up the prospects of a deal being good for the creation of new drugs but AstraZeneca already has a healthy pipeline relative to Pfizer, and reducing competition in the pharmaceutical sector seems a funny way to generate growth in new drugs."
"Accordingly, the board has rejected the proposal," the London-listed firm added.
Pfizer has highlighted the considerable tax advantages from the transaction, which would create a new UK-incorporated holding company.
Outlining his company's defence, AstraZeneca chairman Leif Johansson said it "continues to invest significantly in research, development and manufacturing in the UK, Sweden and the US".
He added: "We are showing strong momentum as an independent company, in particular with our exciting, rapidly progressing pipeline, which the board believes will deliver significant value for shareholders.
AstraZeneca shares traded down 0.35 per cent at 47.98 pounds around midday in London.
Earlier Friday, Pfizer chief executive Ian Read said "the industrial logic for a combination between Pfizer and AstraZeneca is compelling".
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