He studied conducting at the Bucharest Conservatory, and then privately with Silvestri and Lindenberg. He made his conducting debut at the age of seventeen, leading a performance of Gounod's opera Faust in the Rumanian town of Silbiu.
His first professional engagement was as a violinist in the Bucharest Radio Quartet in 1947 and also as a violinist in the Rumanian State Ensemble in 1947. Meanwhile, he had debuted as a conductor in 1946 with the Rumanian State Opera Orchestra. In 1948 he received an appointment as assistant conductor of the Rumanian State Ensemble, which consisted of an orchestra, a chorus, and dancers. He became its musical director from 1950 to 1955.
In 1955 he became principal conductor of the Rumanian State Opera. In 1956 he won the prestigious Besançon Conducting Competition. His Jewish heritage drew him to emigrate to Israel in 1959, where he was soon appointed musical director of the Haifa Symphony Orchestra the same year. In 1960 he founded and was appointed musical director of the Ramat Gan Chamber Orchestra.
He began to appear as guest conductor in Europe, including his British debut, with the London Philharmonic Orchestra in 1960. His first North American appearance was taking the Israel Chamber Orchestra on tour in 1963. In 1965 he appeared with the Philadelphia Orchestra, and he frequently guest conducted at the Royal ballet in London's Covent Garden from 1962 to 1966. He became a favorite for his renditions of Tchaikovsky's and Stravinsky's ballets. In 1966 he resigned from the Haifa Symphony.
In the same year he was appointed musical director of the Göteborg (Gothenburg) Symphony Orchestra in Sweden (remaining there into 1977), and in 1967 he gave up his chamber orchestra position in Israel to become principal conductor of the Northern Ireland Orchestra in Belfast (1967-1968). In 1969 he was appointed music director of the Baltimore Symphony Orchestra, and moved his home to that city in the State of Maryland, USA, a historic east coast port city near Washington, D.C.
In both cities he was credited with making immediate continuous and marked improvements in the orchestras' standards. He stayed in Baltimore for seventeen seasons. Critic Stephen Wigler of the Baltimore Sun said, "The modern Baltimore Symphony was created by Sergiu Comissiona. He became a citizen of the United States in historic naturalization ceremonies held on America's Bicentennial Day, July 4, 1976, and Baltimore's most patriotic site, Fort McHenry, famous as the place the original Star-Spangled Banner was flown during a British bombardment during the War of 1812 between Britain and the USA.
During his tenure in Baltimore, he also was musical director of some music festivals and of the American Symphony Orchestra in New York (1977-1982). When he left the Baltimore Symphony in 1986, he was appointed Conductor Laureate, and continues to make appearances with them.
In 1990 he became Chief Conductor of the Spanish Radio and Television Symphony Orchestra in Madrid, a position that continued until 1998, and from 1990-1994 held the same position with the Helsinki Philharmonic Orchestra. He was associated with shorter appointments with several other orchestras.
Also in 1990 he became Music Director of the CBC Vancouver Symphony Orchestra, and was also Music Director of the Asian Youth Orchestra, which he took on a major European tour. He was characterized by rich, clear, fiery interpretations and a knack for innovative, wide-ranging choices of repertory. ~ Joseph Stevenson, Rovi
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