When the Spaniards arrived, the ruler of the Aztec empire was Moctezuma II , who was later killed. His successor and brother Cuitláhuac took control of the Aztec empire, but was among the first to fall from the first smallpox epidemic in the area a short time later.  Unintentionally introduced by Spanish conquerors, among whom smallpox was endemic, the infectious disease ravaged Mesoamerica in the 1520s. It killed more than 3 million natives as they had no immunity .  Other sources, however, mentioned that the death toll of the Aztecs might have reached 15 million (out of a population of less than 30 million) although such a high number conflicts with the 350,000 Aztecs who ruled an empire of 5 million or 10 million.  Severely weakened, the Aztec empire was easily defeated by Cortés and his forces on his second return with the help of state of Tlaxcala whose population estimate was 300,000.  The native population declined 80–90% by 1600 to 1– million. Any population estimate of pre-Columbian Mexico is bound to be a guess but 8–12 million is often suggested for the area encompassed by the modern nation.