The US Secretary of State made her second intervention in the case amid mounting speculation that the Libyan intelligence agent could be freed today.
She said the American government was "still encouraging the Scottish authorities" to keep Abdelbaset Ali Mohmed Al Megrahi in jail.
Kenny MacAskill, the Scottish National Party justice minister, is considering his release on compassionate grounds.
The 57-year-old Libyan has terminal prostate cancer and has made an emotional plea to be allowed to return home to die with his family. Medical experts say the cancer is aggressive, he is no longer responding to treatment and has less than three months to live.
Megrahi dropped his second appeal against his conviction this week in a move that may help pave the way for his release.
Mrs Clinton, who has already telephoned Mr MacAskill to make her views known, said: "I just think it is absolutely wrong to release someone who has been imprisoned based on the evidence about his involvement in such a horrendous crime."
American relatives of the victims, most of whom are convinced of Megrahi's guilt, say that he showed their loved ones no compassion and should die in jail.
The British families believe the Libyan is innocent and support his release, but have expressed dismay over his decision to end his appeal.
They had hoped that it would reveal new evidence and finally disclose the truth about the bombing in 1988 in which 270 people died.
With Megrahi now destined to die as a guilty man - either at home in Libya or in jail in Scotland - they are appealing again for a full public inquiry into the atrocity.
Alistair Darling, the Chancellor, who is standing in for the Prime Minister while he is on holiday, said he expected the decision soon, but it was entirely up to the Scottish Executive and the UK Government was not involved.
Asked whether it would be easier for British firms to do business with Libya if Megrahi was sent home, he added: "I think the justice secretary has to take the decision on its own merits. He is legally obliged to do that.
"We have always said that we think that Libya will be far better in the international community, that is now happening. I think we have made great strides in convincing Libya that what it was doing in the past wasn't in its interest and wasn't in our interest."
The SNP has been criticised over its handling of the case, but John Swinney, the finance minister, said Mr MacAskill had listened to a wide range of representations and all the evidence would be "properly considered".
He added: "Kenny MacAskill has gone to very significant lengths to listen to everybody's opinion about this case because he realises the seriousness of the decision, the seriousness of the case."
The minister has been asked by the Libyan authorities to consider either freeing Megrahi on compassionate grounds, or allowing his transfer to a prison in Libya.
However, for a prisoner transfer to take place all legal proceedings have to be at an end, and the Crown still has an appeal pending against the Libyan's 27-year sentence on the basis that it was "unduly lenient".
