Xiaobing Yan, 40, and Jian Zhang, 38, who are both in China and have not been taken into US custody, were charged with conspiring to distribute large quantities of fentanyl and fentanyl analogues into the United States, the Justice Department said.
They were charged in separate indictments unsealed on Monday in Mississippi and North Dakota.
"For the first time, we have indicted major Chinese fentanyl traffickers who have been using the Internet to sell fentanyl and fentanyl analogues to drug traffickers and individual customers in the United States," Deputy Attorney General Rod Rosenstein said in a statement.
An analogue is a drug that is chemically similar in makeup to another.
The United States does not have an extradition agreement with China.
Rosenstein said the department has talked to Chinese officials about the cases and plans to share the government's evidence.
China must do more to crack down on labs making the drugs, he said. "We believe that most, if not all, fentanyl that is distributed here in the US and in Canada, originates in China, he said.
Yan operated at least two chemical plants in China that were capable of illegally producing "ton quantities" of the drugs, and evaded detection by systematically altering their chemical makeup, the Justice Department said.
Investigators identified more than 100 distributors in the alleged scheme.
Five Canadians, two residents of Florida and a resident of New Jersey were also charged in connection with the alleged conspiracy involving Zhang, the department said.
Speaking in Beijing, Chinese Foreign Ministry spokesman Lu Kang said he did not know anything about this specific case, but added that the Chinese government took the fentanyl issue seriously and was continuing to cooperate with the United States to fight the illegal production and sale of fentanyl.
Earlier on Tuesday, President Donald Trump said his drug czar nominee, Republican US Representative Tom Marino, had withdrawn his name from consideration.
Marino was cited in a Washington Post-CBS "60 Minutes" report on Sunday as spearheading legislation to neuter the Drug Enforcement Administration's power to crack down on opioid manufacturers who were flooding the market with the addictive painkillers.
That report, however, involved legal prescription drugs that were illegally diverted.
The United States is dealing with a major epidemic of opioid overdoses. In 2016, the Centers for Disease Control estimated that 20,000 Americans were killed by fentanyl, a highly addictive synthetic painkiller.
According to law enforcement officials, the drug is 50 times more potent than heroin and 100 times more potent than morphine.
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