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Guglielmi was born in Massa. He received his first musical education from his father, and afterwards studied under Francesco Durante at the Conservatorio di Santa Maria di Loreto at Naples. His first operatic work, produced at Turin in 1755, established his reputation, and soon his fame spread beyond the limits of his own country, so that in 1762 he was called to Dresden to conduct the opera there. He remained for some years in Germany, where his works met with much success, but the greatest triumphs were reserved for him in England.
He went to London, according to Charles Burney, in 1768, but according to Francesco Florimo in 1772, returned to Naples in 1777. He continued to produce operas at an astounding rate, but was unable to compete successfully with the younger masters of the day. In 1793 he became maestro di cappella at St Peter's, Rome, where he died in 1804.
He was a very prolific composer of Italian dramma giocoso and commedia per musica operas, and there is in most of his scores a vein of humour and natural gaiety not surpassed by Domenico Cimarosa himself. In opera seria he was less successful. But here also he shows at least the qualities of a competent musician. Considering the enormous number of his works, his unequal workmanship and the frequent instances of mechanical and slipshod writing in his music need not surprise us.
He also wrote oratorios and miscellaneous pieces of orchestral and chamber music. Of his eight sons two at least acquired fame as musicians: Pietro Carlo Guglielmi (1763-1827), a successful imitator of his father's operatic style, and Giacomo Guglielmi, an excellent singer.