The unseeded Indian lost 5-7 5-7 to his "good friend" in what was their first encounter on the circuit.
Faced with an opponent ranked more than 100 places above him in the ATP list, Somdev fought well in the opening set, saving as many as six break points.
But he could never really pile the pressure on Isner, who, in the end, managed to get the crucial break while holding his own serve to pocket the set.
The local favourite increased his dominance in the second set, sending down nine aces in the process. Once again, Isner managed to break Somdev once out of the three chances he earned to seal the issue.
He will next face Cypriot Marcos Baghdatis in the quarterfinal.
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