Djokovic has not played since his shock second round exit at the Australian Open in January, and showed signs of ring-rustiness before defeating Klizan 6-3, 7-6 (7/4) before a raucous Mexican crowd.
The 29-year-old Serbian started slowly and was forced to save two break points in the third game of the first set before hanging on for a 2-1 lead.
He had to save a further break point in the fifth game to take a 3-2 lead but then swiftly punished world number 62 Klizan with a break to go 4-2 up.
The contest then went with serve as Djokovic claimed the opening set.
Klizan was soon in trouble in the second set as he suffered a break in the opening game before Djokovic held for 2-0.
