The 57-year-old actress will portray Madoff's wife, Ruth Madoff, with actor Robert De Niro as the real-life former investment advisor. Alessandro Nivola will play the couple's elder son, Mark Madoff, who hanged himself at age 46 in December 2010.
The HBO television movie is based on the Diana B. Henriques book of the same name, with additional sourcing from Truth and Consequences by Laurie Sandell. Barry Levinson, who directed Jack Kevorkian biopic You Don't Know Jack for the network, will helm the film.
The movie has long been in the works at HBO, with De Niro attached since 2011. The dramatization will explore Madoff's infamous Ponzi scheme, which swindled clients of $65 billion and landed the financier a 150-year prison sentence.
The role marks Pfeiffer's first on television since she played a client on CBS drama Picket Fences in 1993. The actress is known for starring in such films as Batman Returns, The Age of Innocence and White Oleander, and last appeared in the 2013 movie The Family.