We have previously demonstrated that cells of murine T-cell lymphoma, when grown in vivo or in vitro in an environment of high cell density, undergo phenotypic alterations, providing them with survival benefits. However, it is unclear whether the acquisition of such growth-related phenotypic alterations is inheritable in successive cell generations and if these alterations are associated with an irreversible alteration in their tumorigenic ability and evolution of multidrug resistance. To investigate this, tumor cells of a murine model of a T-cell lymphoma, designated as Dalton's lymphoma, and obtained from high and low cell density environment in vitro and in vivo, were transplanted in mice with or without the administration of anticancer drugs followed by analysis of their phenotypic properties and tumorigenic potential as measured by kinetics of tumor growth and survival of the tumor-bearing host. Kinetics of tumor progression was comparatively rapid in tumor-bearing mice transplanted with tumor cells from a high cell density environment, causing an early death of the host. Moreover, under these conditions the antitumor response of anticancer drugs, cisplatin, doxorubicin, and methotrexate, was found to be less effective compared with mice transplanted with tumor cells from a low cell density environment. The tumor cells from a high cell density source showed a long-term alteration in their survival properties both in vitro and in vivo, indicating that such alterations were sustainable over successive cell cycles. The study also discusses the possible mechanisms indicating the role of MDR1, Hsp70 and 90, Bcl-2, IL-1, IL-6, IL-10, IFNγ, and TGFβ in the evolution of multidrug resistance in tumor cells obtained from a high cell density environment.