It has called upon residents to send a message to the local authority before a decision is taken on the scheme next month.
The plans, which could see the creation of a new multiplex cinema, restaurants and shopping parade, have divided opinion in the town.
Supporters say that the proposals are a once in a lifetime opportunity to bring the town into the 21st Century. But opponents argue that they could harm business for independent traders and are out of keeping with the town's historic buildings.
The Express launched its referendum with a front page appeal to readers as well as three inside pages on the proposals and the arguments for and against.
Editor Gareth Tidman said: "This is one of the biggest decisions affecting Macclesfield and we will be living with the outcome for years to come.
"As a paper we have taken a strict neutral stance on the scheme, but felt that it is important the people of Macclesfield get the chance to say whether they want it or not.
"There is genuine excitement in the town over how our poll will go."
To vote, readers will have to fill in coupons printed in the paper and return them to the newsroom.
No photocopies are allowed and the paper will only accept one entry per envelope to stop any individuals having an undue influence on the outcome.
Sales of the paper were boosted in November last year when the paper published an eight page in-depth pull out on the plans.
Cheshire East Council's planning committee is due to vote on the plans on June 12.
