An inverse correlation between p27(Kip1) expression and proliferation has been recently established in tissues derived from human lymphomas. The nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)/phospholipase C-gamma (PLCgamma) complex also appears to play an important role in cell proliferation and malignant transformation of anaplastic large cell lymphoma (ALCL). In this study, we report that SUDHL-1 and KARPAS 299 ALCL-derived cell lines present different sensitivity to the antiproliferative effect of recombinant adenovirus-mediated p27(Kip1) expression or to serum-starvation in culture media. The results indicate that exogenous p27(Kip1) may interact with the NPM-ALK/PLCgamma pathway in SUDHL-1 but not in KARPAS 299 cells. This interaction correlates with changes in cell cycle and cell morphology observed mainly in SUDHL-1 cells. The percentage of SUDHL-1 cells in S phase declines, whereas it is almost unchanged in KARPAS 299 cells as compared to the controls after 96 h of infection with the recombinant adenovirus. Furthermore KARPAS 299 cells are resistant to serum-starvation due to deficient p27(Kip1)-upregulation and G1 arrest, whereas SUDHL-1 cells respond with increased G1 phase and p27(Kip1)-upregulation after 48 h of serum-starvation. Both cell lines express appropriate variation of levels of cyclins E and A, and Rb-phosphorylation as expected by growing them in culture media with different FBS content. Although both cell lines express cyclin D2, SUDHL-1 cells only present high level of cyclin D3. Moreover SUDHL-1 cells express high level of PTEN and the PKB/Akt pathway is constitutively activated in both cell lines. Lastly SUDHL-1 cells show higher levels of phosphotyrosine-containing proteins that is correlated with a higher NPM-ALK-associated autophosphorylation activity compared to KARPAS 299 cells. Our study clearly identifies some of the biochemical differences that may explain the difference in sensitivity to antiproliferative stimuli shown by two cell lines derived from the same type of lymphoma.