Ruto's meeting with Zambia President Hakainde Hichilema will explore establishing a Joint Trade Committee to address non-tariff barriers.
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The president will also use the forum to rally support for Kenya's bid for the African Union Commission chairperson post.
This year's summit marks the 30th anniversary of COMESA, a key trading bloc with a market of 640 million people and a GDP of $1 trillion.
Between 2019 and 2023, Kenya's exports to COMESA grew by 8.9 per cent, highlighting the potential for regional trade and integration.
The COMESA Heads of State summit is an annual event, which took place in Zambia last year.