The impact of initial fludarabine therapy on transformation to Richter syndrome (RS) or prolymphocytic leukemia (PLL) in patients with chronic lymphocytic leukemia (CLL) is uncertain. We studied the outcomes of 521 patients with CLL who were randomized to initial fludarabine (F), chlorambucil (C) or F + C therapy on an intergroup trial (CALGB 9011). RS developed in 34 (7%) patients and PLL in 10 (2%). RS and PLL occurred in 14 (7%) and three (2%) of 188 patients randomized to F; nine (5%) and four (2%) of 191 patients treated with C; and 11 (8%) and three (2%) of 142 receiving F + C, respectively. Four percent of the 206 patients with Rai stage III/IV developed PLL, compared to only 1% of the 315 patients with Rai stage I/II (p = 0.02). Initial fludarabine therapy in patients with CLL did not impact transformation to RS or PLL, nor were any other baseline characteristics predictive for such transformation in this series.