Cortez - Mexico - Aztecs. Pizarro - Peru - Incas.
But in both cases the Spanish took advantage of bitter divisions among the natives to make their conquest, helped greatly by massive epidemics that disorganized the native empires.
Even with their stone age tech, it is highly unlikely the Spaniards could have conquered either Mexico or Peru if these empires had been united and healthy.
Point not addressed. Some modern flues are descended from the flue virus of 1918. There is also the bubonic plague http://www.freerepublic.com/focus/f-chat/2792352/posts and any number of bioweapon possibilities.
How ruthless a campaign do we want?