The remarks came after allegations by the US linking ISI to attacks on its forces by the Haqqani network.
Referring to the allegations by US officials, Gilani said the message emanating from Washington seemed to be “they can"t live with us, they can"t live without us".
“So, I will say to them that when they can"t live without us, they should increase contacts to end misunderstandings with us" related to war on terrorism, he told reporters in Karachi.
“If the relations with the US are on the basis of mutual respect and mutual interest, and if there is such wrong messaging, then it is difficult to convince our people. I would ask America to leave political space for us so that we can convey their importance to the people," he said.
Gilani"s remarks appeared more conciliatory than the statements of Foreign Minister Hina Rabbani Khar, who told Geo News channel in New York that the US risked losing its partnership with Pakistan if it continued criticising Islamabad for the alleged link between the ISI and Haqqani network.
“We have a strong stand and… we have conveyed to the US that you will lose an ally. You cannot afford to alienate Pakistan, you cannot afford to alienate the Pakistani people.
If you are choosing to do so, and if they are choosing to do so, it will be at their (United States") own cost," Khar said.
The Pakistani leaders spoke a day after outgoing US military chief Admiral Mike Mullen accused the ISI of supporting the Haqqani network in carrying out a string of deadly terror attacks, including an assault on the US embassy in Kabul on 13 September.
Mullen said the Taliban faction was a “veritable arm" of Pakistan"s spy agency.
During his interaction with the media, Gilani contended that Pakistan was not “isolated in our relations" with the world community.
“We have good relations with the whole world. In our region, we have relations and we have good relations with our neighbours," he said.
Defence Minister Chaudhry Ahmed Mukhtar too rejected the US accusations and said there would not have been an attack on an army general in Pakistan"s border areas if there were contacts between the security establishment and Haqqani network.
He was referring to a recent incident in which a Major General commanding troops in the country"s northwest was injured when militants fired at his helicopter.
“At this time, it is difficult for America to move away from Pakistan and we too need them… We have had a relationship with them from the 1940s and do not want to end that," Mukhtar said.
“We will take action jointly (against terrorists) and if the Americans select their own target, it will be our effort to tell them it is a wrong target," he added.
Mullen"s accusations and response of the Pakistani leaders reflect an escalation in the war of words between the troubled allies in the war on terror.
The relationship between the two countries has been bumpy since the beginning of this year, when a CIA contractor was arrested in Lahore for gunning down two men linked to the ISI.
The ties plunged to a new low after the covert US raid that killed Osama bin Laden in the Pakistani garrison city of Abbottabad on 2 May.
Since then, the US has stepped up pressure on Pakistan to act against the Haqqani network, which is based in the North Waziristan tribal region.