Del Potro returned to competition after a four-month absence at the Delray Beach Open last week but, with his knee heavily strapped, looked unable to move around freely and lost in the quarter-finals to American Mackenzie McDonald.
He subsequently withdrew from this week's Acapulco Open.
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"I am truly disappointed that I will not be able to return ... to defend my title," Del Potro said of the Masters 1000 event that starts on March 7.
"It is one of my favourite tournaments, and I have incredible memories from last year, but my doctors have advised me to rest. I hope to be back on court soon."
The Argentine saved three championship points on the way to upsetting Roger Federer in last year's final.
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