Under the stage name of Porfirio Pacchierotti, he made his début in Baldassare Galuppi's opera Le nozze di Dorina at the Teatro dei Nobili in Perugia during the carnival season of 1759, playing, as young castrati often did, a female role: Livietta.

His first success as primo uomo (lead male singer) was in that composer's Il re pastore, in which he first sang the role of Agenore at the Teatro San Benedetto, Venice, in the summer of 1769.

In 1770, he was at Palermo, where he sang alongside the famous and notoriously capricious soprano, Caterina Gabrielli, whose every feat of virtuosity he not only equalled but so far surpassed that he earned that redoubtable lady's admiration.

Because of Ruffo's royal connection (and also because, as a nobleman, he was immune from prosecution), the poor singer spent several days in prison, but apparently the noble youth himself obtained his release.

There is another version of this story in which Ruffo was the lover (cavalier servente) of a certain Marchesa Santa Marca, who had become infatuated with Pacchierotti on hearing him sing in Schuster's Didone abbandonata.

In Milan, he famously appeared at the inauguration of the Teatro alla Scala on 3 August 1778, taking the protagonist's role of Asterio in Europa riconosciuta by Antonio Salieri.

One of the former, Lord Mount Edgcumbe, left a detailed description of the singer's many merits: Pacchierotti's voice was an extensive soprano, full and sweet in the highest degree: his powers of execution were great, but he had far too good taste and good sense to make a display of them where it would have been misapplied, ... conscious that the chief delight of singing and his own supreme excellence lay in touching expression and exquisite pathos.

... As an actor, with many disadvantages of person ... he was nevertheless forcible and impressive ... His recitative was inimitably fine, so that even those who did not understand the language could not fail to comprehend, from his countenance, voice and action, every sentiment he expressed.

Known as "sweet Pacc" to Susanna and her sister Fanny (herself a well-known author and later Madame d'Arblay), he also earned their respect during the anti-Catholic Gordon Riots of June 1780 by refusing to remove his name from his door and, though an Italian Catholic, insisting on walking the streets openly while the mob yelled "No Popery!"

This was of a cantata entitled Il tributo, by a fellow castrato, Venanzio Rauzzini, long settled in England, and took place at Beckford's mansion Fonthill Splendens, near Bath.

His first appearance on his final return to Italy was for the inauguration of another opera house: the new Teatro la Fenice in Venice, where on 16 May 1792 he sang the leading role of Alceo in I giuochi d'Agrigento by Paisiello alongside Brigida Banti.

On 28 June 1814, he underwent the emotional experience of singing in Saint Mark's Basilica in Venice at the funeral service held in honour of his old friend and favourite composer, Ferdinando Bertoni.