Rex Tillerson and Sergei Lavrov's talks got off to a frosty start
The pair told a news conference in Moscow that they had tried to seek common ground on a range of issues in a "frank" discussion.
But Mr Tillerson fired back that "There is a low level of trust between our two countries.
Adding:"The world's two foremost nuclear powers cannot have this kind of relationship."
Mr Tillerson and Mr Lavrov met with Vladimir Putin to discuss a range of issues.
In a round of tense talks, one of the most pressing issues on the table was the chemical gas attack in Syria and the ensuing strike by the US on a Syrian air base.
Both disagree on the approach to Syria and traded words over what exactly should be done.
Mr Lavrov said: “We have talked about the ensuing missile attack by the US against the air base on April 7th. We have stated our position on many occasions. We think there needs to be a thorough investigation into this incident."
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Mr Tillerson said it was “conclusive” that Syrian president Bashar al-Assad’s regime was behind the chemical attack that took 87 people's lives.
But Russia insists that there should be an investigation.
Mr Lavrov said: “As for the investigation into the incident, there is a fact-finding mission of the OPCW, there is also a joint mechanism for an investigation set out together by the OPCW and the United nations.”
Lavrov issued a warning to Tillerson Wednesday against any further US strikes on the Syrian regime
Mr Tillerson said that he was keen to see Mr Assad removed.
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He reiterated the U.S. position that Syrian President Bashar al-Assad must eventually relinquish power in Syria, a position starkly at odds with Russia.
He said: “The final outcome in our view does not provide a role for Assad or for the Assad family in the future governance of Syria.
This view is a change from his stance just two weeks ago, when he said removing Assad was not a priority.
He added that the reign of the Assad family is “coming to an end, and they have brought this on themselves.
He said Assad needs to be ousted in an “orderly” way.
Vladimir Putin met US Secretary of State Rex Tillerson in Moscow
But Mr Lavrov argued that this would only help Islamic militants.
Russia did not pull any punches with the US during this crucial visit.
Mr Lavrov said Russia "saw some very troubling actions regarding the attack on Syria."
"We believe it is fundamentally important not to let these actions happen again."
Mr Tillerson reiterated the U.S. position that Syrian President Bashar al-Assad must eventually relinquish power in Syria, a position starkly at odds with Russia.
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The talks were a test of US-Russia relations which have been marred with questions over Syria, and alleged meddling in the US elections.
Mr Lavrov said that the U.S. had provided no evidence that it interfered in the 2016 election despite repeated requests.
“We want to hear concrete proof and then we will respond accordingly,” Mr Lavrov said.
This was Mr Tillerson's first trip to Russia as Secretary of State.
It was also the first official trip by a prominent member of Mr Trump's cabinet.
Mr Lavrov said after talks with the US Secretary of State that some progress had been made on Syria and that a working group will be set up to examine the poor state of U.S.-Russia ties.