Clonal plasma cells from patients with multiple myeloma (MM), plasma cell leukemia (PCL) and human myeloma cell lines (HMCLs) were analyzed for deletions/mutations of the tumor suppressor gene PTEN. By interphase-FISH, hemizygous PTEN deletions were detected in 4 (5.6%) of 71 MM patients, 2 (20%) of 10 PCLs, and 2 (20%) of 10 HMCLs. PTEN deletions were detected in 4 MM patients at diagnosis with stage III disease (Durie-Salmon). Of the six cases with PTEN deletions, 1 MM had a 13q deletion, 1 PCL had a t(11;14), and the other PCL had a t(14;16), a 13q deletion and a p53 deletion. Sequencing analysis did not detect PTEN mutations in 11 primary MM and 5 PCL cases. Our results indicate that alterations of PTEN are uncommon in MM patients, and PTEN deletions tend to occur in advanced disease suggesting that they are secondary, rather than primary, events in the pathogenesis of MM.