Mathieu, making his return to ATP World Tour action after taking a year off while recuperating from a knee injury, bested the favored Lopez 4-6, 7-6 (7-5), 6-4 on the event's opening day.
The Frenchman improved to 5-3 all-time against Lopez.
Meanwhile, fifth-seeded Richard Gasquet moved on with a 6-3, 1-6, 6-1 victory over Italian Flavio Cipolla, and No. 6 seed Alexandr Dolgopolov of Ukraine was upended by Poland's Lukasz Kubot 6-7 (4-7), 6-4, 6-2.
Also Monday Jesse Huta Galung of the Netherlands defeated Ivan Ljubicic of Croatia 7-6 (8-6), 6-3.
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