Father Eyzaguirre went back to South America, collected some money, and returned to Rome with a few students. He rented a small house for these students and some others who arrived later. They were fifteen in all. Pius IX ordered the Fathers of the Society of Jesus to direct the new college, and they opened the college on 21 November, 1858. In December, 1859, Pius IX helped to purchase a larger house, belonging to the Dominican Order, near their Church of the Minerva. He also bought with his own money a villa and a vineyard for the use of the college, and made Monsignor Eyzaguirre protonotary-apostolic. Towards the beginning of 1860 he sent this prelate back to South America as ablegate of the Holy See, to urge the bishops again to co-operate on a larger scale in procuring the necessary means for the support of the college. At the same time he himself contributed a large sum of money to the new house.
During the year 1864 Pius IX sent to the college books from his own private library, ordered a new chapel to be erected at his own expense, and furnished it with vestments and on the 21 November, the sixth anniversary of its foundation, visited the college in person. He is considered the principal, if not the first, founder of the South American College.
The number of students continually increasing, the superiors had to look for another dwelling. Through the assistance of Cardinal Sacconi, protector of the college, part of the old novitiate of the Jesuits, on the Quirinal -- which since the year 1848 had been used for a French military hospital -- was secured, the house near the Minerva sold, and the new residence occupied on 18 April, 1867, the feast of the Patronage of St. Joseph, to whom the college had been dedicated.
South American bishops visiting Rome brought new students, and the number reached fifty-nine. Pius IX, almost unannounced, went to the new college, assisted at an "academy", and allowed his name to be added to its legal title, making it Collegio Pio-Latino Americano.
In 1870 the bishops attending the First Vatican Council increased the number of students to eighty-two. In 1871, the Italian government having expelled the Jesuits from the small part of the novitiate they occupied, acceded to the request of the Brazilian Emperor and permitted the South American College to remain where it was until a suitable house should be found. The new rector the Rev. Agostino Santinelli, S.J., bought a new site in the Prati di Castello, not far from the Vatican, and near the Tiber. The foundation stone was blessed on 29 June, 1884, by the protector, Cardinal Sacconi, in presence of a large assemblage among whom was the Most Rev. Father Peter Beckx, General of the Society of Jesus, then living in the American College. The work of building began immediately, and Father Santinelli saw the building finished in 1887-88.
It was here that the first General Council of Latin America (28 May-9 July, 1899) was held. There were present fifty-three prelates, archbishops and bishops, of whom twenty-nine took up their quarters in the college, together with their secretaries and servants. The solemn opening took place in the college chapel, and all the sessions were held there. In the same chapel on 26 March, 1905, the Cardinal Protector, Joseph C. Vives y Tuto, solemnly published the Apostolic Constitution "Sedis Apostolicae providam", by which His Holiness granted the title of "Pontifical" to the college and committed its direction in perpetuum to the Society of Jesus. Aloysius Caterini, S.J., Provincial of the Roman Province, accepted the charge in the name of the General of the Society, absent through sickness.
A number of the seminaries and one ecclesiastical university in Latin America took their professors exclusively from the alumni of the college. The first cardinal of Latin America, Joaquin Arcoverde de Albuquerque-Cavalcanti, Archbishop of Rio de Janeiro, studied there.