"This is the first thing I've ever done in baseball that I didn't have a high level of success at," MacPhail said, his voice cracking.
The Cubs have made only two playoff appearances since MacPhail joined them in 1994 after he spent nine years with the Minnesota Twins, helping them to two World Series titles. Chicago finished 66-96, worst in the National League.
"The clock on the MacPhail-o-meter has run down to zero," said MacPhail, who told reporters he broached the subject of resigning during a team review with Tribune Co. executives in midseason.
Marketing vice president John McDonough will take over the club's day-to-day operations on an interim basis.