By the dawn of the 1950s, Reed had established himself as a popular local musician and joined the Gary Kings with John Brim, as well as playing on the street with Willie Joe Duncan. Reed failed to gain a contract with Chess Records, but then signed with Vee-Jay Records through Brim's drummer, Albert King. At Vee-Jay, Reed began playing again with Eddie Taylor and soon released "You Don't Have To Go", his first hit song. This was followed by a long string of hits. Reed maintained his reputation, in spite of rampant alcoholism. Most memorably, Reed once urinated on another performer's dress at the Apollo Theater. Sometimes, his wife had to help him remember the lyrics to his songs while performing them. In 1957, Reed developed epilepsy, though the disease was not correctly diagnosed for a long time, as Reed and doctors assumed it was delirium tremens.
In spite of his numerous hits, Reed never achieved the same level of critical success as other popular blues artists of the time, though he had more hit songs than any others. When Vee-Jay Records went under, Reed's manager scored a contract with the fledgling ABC-Bluesway label, but Reed was never able to score another hit.