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Brown was born in Meridian, Mississippi, and sang in church as a child. In 1919 her family moved to Chicago and she began studying piano. In the early 1920s she began taking gigs in clubs and broadcast on radio. From the 1930s to the 1950s she toured the United States regularly, recording for Decca Records (among other labels) along the way and recording many humorous, ironic titles such as "Breakin' in a New Pair of Shoes", "Mama Don't Want No Peas and Rice and Coconut Oil", "When Hollywood Goes Black and Tan", and "The Stuff Is Here and it's Mellow". Her stride piano playing was often compared to Fats Waller.
In the 1940s, Brown began to shy away from singing bawdy blues songs because of her deepening religious beliefs and, in 1953, she retired and became a nurse. The song "Sweet Cleo Brown" was recorded by Dave Brubeck in tribute to her. She was rediscovered, living in Colorado, in the 1980s after being tracked down by Marian McPartland. She returned to record again, and performed on National Public Radio.
Some of Brown's earliest recordings have been reissued by Document Records.
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