While the inhabitants of the Antisuyu region were most likely to have been divided among any number of tribes, both the Inca and the Spanish generalized their consideration for the natives by referring to them as a sole nation: the "Antis". Incan interaction with these people began under the reign of Viracocha, the eighth Sapa Inca, who conquered an area east of Qosqo which would included Ollantaytambo, gateway to the jungle region.

The Antis were frequently thought of as violent, savage jungle dwellers. Whether for a particular attack by the Antis into the Sacred Valley or the possibility of such a pending attack, Viracocha's successor Pachacuti built fortresses at Ollantaytambo and at Saqsaywaman (Qosqo) to defend against eastern offenses.

As he set about the creation of an Andean empire, Pachacuti arranged for campaigns to subdue the Antis and incorporate their lands. Inca lore states that a large expedition traveled deep into the jungles to defeat the Kingdom of the Mojos along the Amaru Mayu, the Serpent River (possibly today's Madre de Dios River). Here they encountered and battled the fierce warriors called the Chunchos (Savages), with the outcome unknown.

Whether or not the prior account is valid, the Inca apparently held some claim over Antisuyu by the end of Pachacuti's life. At the start of his son's reign, that of Tupac Inca Yupanqui, the Antis were called upon to pay homage to the new Sapa Inca and thereby submit to Incan authority. The Antis chieftans rebuffed these demands and rebelled against their inclusion in Tawantinsuyu. This act prompted Tupac to organize a full invasion of Antisuyu.

Tupac himself led this campaign, splitting his army into three groups which entered into the forests. Disoriented by the thick vegetation, the Inca took to subjugating villages and then building roads to reach these newly acquired possessions. By this manner, they made gradual advance into the region.

Yet the hot and humid climate of Antisuyu antagonized the Inca, far more than the resistance of the Antis. Accustomed to the moderate climate of the Andean highlands, the Inca succumbed to rampant disease and death. Nearly a third of Tupac's warriors were lost as a result of disease in the Antisuyu invasion. With the reports of rebellion in Collasuyu, Tupac and a majority of his remaining forces withdrew. One might question whether the overwhelming obstacles presented by the Antis, or more so their lands, were not too many for the Sapa Inca to bear. Without greater incentives to conquer further, the Inca carved out only a small portion of the Amazonian jungle for inclusion in the empire.

What is verifiable is the admittance of Antisuyu into the Incan Empire, regardless of the fact that the Inca never actually defeated the Antis. There was a veracity of trade in and out of the jungle quarter. The metals, textiles and utencils of the Inca were imported in exchange for the hardwoods, exotic animals, cacao, vanilla, wax and other goods of Antisuyu. Additionally, the Antis archers accompanied the Incan army on campaigns as far north as present-day Quito, Ecuador.

The ferocity of Amazonian tribes is legendary, and the Antis were no exception. Both the Inca, and the Spanish to follow, found conquest of these tribes to be an unnecessary, if not impossible, burden. Instead, the use of commerce and token domination was the manner by which the Antis were merged into Tawantinsuyu.

• History of Tambopata
• History of the Inka