Abadula Gemeda was the speaker of the House of People's Representatives from 2010 and was previously army chief of staff and president of the country's most-populous region, Oromia.
"I have submitted a letter of resignation to the House of People's Representatives and the concerned body to quit my job as the speaker of the House," he told a press conference.
"I don't want to continue in this position and I have lost interest," he said, adding that he would disclose the precise reasons for his departure once his resignation is accepted.
The OPDO is one of four ethnically based parties that comprise the ruling Ethiopian People's Revolutionary and Democratic Front (EPRDF) coalition, which together with its allies controls all seats in Ethiopia's parliament.
Oromia was rocked by anti-government protests that started in late 2015 and soon spread to neighbouring regions, prompting the government to declare a nationwide state of emergency that was repealed in August.
Last month, clashes broke out along the border between Oromia and neighbouring Somali region, killing hundreds and displacing at least 50,000 people.
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