Mantle cell lymphoma (MCL) is molecularly characterized by bcl-1 rearrangement and cyclin D1 gene overexpression. Some aggressive variants of MCL have been described with blastic or large cell morphology, higher proliferative activity, and shorter survival. The cyclin-dependent kinase inhibitors (CDKIs) p21^Waf1 and p16^INK4a have been suggested as candidates for tumor-suppressor genes. To determine the role of p21^Waf1 and p16^INK4a gene alterations in MCLs, we examined the expression, deletions, and mutations of these genes in a series of 24 MCLs, 18 typical, and 6 aggressive variants. Loss of expression and/or deletions of p21^Waf1 and p16^INK4a genes were detected in 4 (67%) aggressive MCLs but in none of the typical variants. Two aggressive MCLs showed a loss of p16^INK4a expression. These cases showed homozygous deletions of p16^INK4a gene by Southern blot analysis. An additional aggressive MCL in which expression could not be examined showed a hemizygous 9p12 deletion. Loss of p21^Waf1 expression at both protein and mRNA levels was detected in an additional aggressive MCL. No p21^Waf1 gene deletions or mutations were found in this case. The p21^Waf1 expression in MCLs was independent of p53 mutations. The two cases with p53 mutations showed p21^Waf1 and p16^INK4a expression whereas the 4 aggressive MCLs with p16^INK4a and p21^Waf1 gene alterations had a wild-type p53. p21^Waf1 and p16^INK4a were expressed at mRNA and protein levels in all typical MCLs examined. No gene deletions or point mutations were found in typical variants. Two typical MCLs showed an anomalous single-stranded conformation polymorphism corresponding to the known polymorphisms at codon 148 of p16^INK4a gene and codon 31 of p21^Waf1 gene. These findings indicate that p21^Waf1 and p16^INK4a alterations are rare in typical MCLs but the loss of p21^Waf1 and p16^INK4a expression, and deletions of p16^INK4a gene are associated with aggressive variants of MCLs, and they occur in a subset of tumors with a wild-type p53 gene.