Speaking to the BBC, the normally diplomatic Lee hinted that his country's loyalties to both Beijing and Washington could one day be tested.
"If America, China relations become very difficult, our position becomes tougher because then we will be coerced to choose between being friends with America and being friends with China," he said. "That's a real worry. Right now we are friends with both — it's not that we don't have issues with either, but we are generally friends with both, and the relationships are in good working order."
The prime minister then told the BBC interviewer that he was "sure" the Chinese were committing "close and sustained attention" to their relationship with Washington, but he said that he hopes "they will have that attention" in the U.S. government given its other global concerns.
"Unless you focus on this relationship — both the win-win aspects as well as the areas where you're in contention — it can go wrong," he added.
Patrick Chovanec, chief strategist at Silvercrest Asset Management, said that it was rare for Lee to speak so bluntly about a trade-off between the U.S. and China.
In a December speech, Lee had previously warned Singapore would be "in a very difficult spot" should U.S.-China relations grow tense.
Fears of a U.S-China trade war are high and should President Donald Trump act on his campaign promise of imposing tariffs on the mainland, a country he blames for the loss of American jobs, global exports and imports may get hit. Singapore, home to one of the world's busiest ports, stands to particularly suffer as its economy is heavily reliant on international trade.
"Singapore is clearly deeply annoyed at the U.S. abandoning TPP," said Chovanec, referring to the Trans-Pacific Partnership trade agreement that was scuttled by the Trump administration.
Before the U.S. presidential election, Lee was "already quite outspoken" in saying that Trump's decision to abandon the deal would hurt the U.S. and its credibility in the region, Chovanec explained.
"Singapore is more important than it might seem, at first glance, because of the quiet but strategically important security relationship it already has with the U.S., which relies on Singapore as a regional supply base for naval operations," he said.
"If abandoning TPP, along with other moves, cause Singapore and other countries in Asia to see the U.S. an unreliable partner, the implications could be quite serious."