Guido Deiro left his home to avoid an arranged marriage, and defying his father’s wishes that he manage the family businesses, he became a professional entertainer and took engagements in France and Germany playing the chromatic accordion. His success as a performer led the Ronco-Vercelli accordion company in Italy to ask him to demonstrate their new piano-accordions at the Alaska-Yukon-Pacific Exposition in 1908. This world’s fair was held in Seattle from June to October 1909. After the fair, he stayed on in Seattle working as a musician in saloons. By this time, he had become a virtuoso at playing a piano accordion. In 1910 he was discovered by an agent for the Orpheum Vaudeville Circuit. His opening debut was at the American Theatre in San Francisco (managed by Sid Grauman) on June 15, 1910. He became an immediate sensation, and began traveling the vaudeville circuit routinely back and forth across the United States and Canada (and other countries as well) as a headliner. During his travels, he met and became friends with another famous Italian accordionist: Pietro Frosini. In addition to playing the popular hits of the day and light classical and operatic fare, Guido Deiro composed his own original compositions. In 1911, Deiro wrote the hit song Kismet. Kismet became the theme song of a successful Broadway musical (1911) and was also featured in two Hollywood movies (1921, 1930). During his lifetime, he recorded more than 110 songs (primarily for Columbia Records, and occasionally for Edison phonograph cylinders). The records were enormously popular, and, along with his vaudeville stardom, helped to propel Deiro to the status of a minor celebrity in American culture.

Throughout the teens and well into the 1920s, Guido Deiro was a dominant voice of accordion. As Deiro showcased the piano accordion through his vaudeville performances across the United States, more and more people were introduced to the instrument, the popularity of the accordion increased. In 1928, Deiro was featured in an early sound film, Vitaphone #2968, titled GUIDO DEIRO: The World’s Foremost Piano-Accordionist. He appeared as an accordionist in several other motion pictures, such as the musical Shine on Harvest Moon and the Carole Lombard comedy The Other Man. Guido Deiro continued to play vaudeville shows until at least 1935 and performed on two world tours, although after 1929, he traveled less and focused his career on the west coast of the United States. During the 1930s, he opened a number of accordion studios and taught and sold accordions. He also gave musical coaching to a young virtuoso accordionist-entertainer from Fresno, California: Dick Contino. After World War II, he lost most of his studios. He became ill in 1947, and died of congestive heart failure in 1950.