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Refregier was born in Moscow and emigrated to the United States in 1920. After working various odd jobs, he earned a scholarship to the Rhode Island school of Design in 1921. After finishing school, Refregier moved back to New York in 1925. To earn a living, Refregier worked for interior decorators doing copies of Bouchers and Fragonards. He continued on his journey and traveled to Munich in 1927. While in there he studied under Hans Hofmann, who worked in abstract expression.
Refregier returned to New York during the late 1920s and lived in Croton-on-Hudson's Mount Airy artists' colony. In an interview Refregier referred to this time as the most wonderful period of his life in spite of the fact that it was wonderful in a peculiar way. He was referring to the depression of the 1930s. Refregier learned a lot about life during these times. He also learned about the United States economy and government.
Refregier found inspiration in tragic events. Refregier was quoted as saying that “the richer we [were] in possessions, the poorer we became in their enjoyment.” He said the amazing part of that period was the “human quality, the humanist attitude that [everyone] had” and the discovery that “the artist was not apart from the people.”
He struggled as a muralist until the government began the Works Progress Administration (later “Works Projects Administration”, WPA) in 1936 that helped create a sponsorship for the arts. When asked about the program Refregier said that it was “by the wisdom of one of the greatest Presidents we ever had, Roosevelt, it's common knowledge the WPA, a relief program, was established [because] it was necessary to protect the skills of the American people.” Refregier received $23.86 a week on the WPA rolls.
Refregier was a faculty member and Chairman of the Board at the American Artists School from 1937-38. Refregier began to gain notoriety and was given the opportunity to choose between two assignments for his first project. The WPA gave him the option of painting a courthouse or the children's ward of a hospital. Refregier chose the children's ward because did not want to have the pressure that came with designing artwork for a courthouse. He was assigned to work on Brooklyn's Green Point Hospital. The project took a little over a year to complete and involved five other contributing artists. After completing the hospital, Refregier's work progressed mainly to government-sponsored projects. These included the World's Fair Federal Works Buildings in the 1933 Chicago World's Fair and the Section of Fine Arts of the Public Building Administration in the Treasury Department. He also worked as a teacher, supervising artist, and mural supervisor.