Bulger walked into the courtroom in shackles, and nodded to his brothers, William and John, who were seated in the front row.
The 81-year-old alleged mob boss spent 16 years on the run before being arrested last month in Santa Monica. Prosecutors say Bulger, the reputed former leader of the Winter Hill Gang, was involved in the string of murders meant to eliminate gang rivals and silence potential witnesses.
An FBI informant said he escaped arrest after an agent tipped him off about a separate indictment, which has since been dismissed.
Wednesday's court appearance was the first time Bulger has responded to the federal murder charges.
The Associated Press contributed to this story