"When they are out of government, even when you are not doing family and friends, they say it is a family and friends government," he said in Bolga after leading a Unity Walk on Saturday.
"Then when they come into government they appoint all their relatives into government and when you talk, they say 'oh it doesn't matter, it is whether they are qualified.'
He quizzed: "Who doesn't have relatives who are qualified?"
"I have plenty relatives who are qualified who could have served in my government but they fact that you are president does not mean you must laod your government with your relatives."
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In the lead-up to the 2016 polls, leading figures of the New Patriotic Party (NPP) accused Mr Mahama of running a "family and friends" government.
They also accuse him of giving juicy contracts his brother Ibrahim Mahama.
Here's the number of family and friends Nana Addo appointed in 2017.