Abstract Transplantable BALB/c and AKR lymphomas of different cell surface immunologic phenotypes have distinctive patterns of response to the ADA inhibitor DCF in vivo and in vitro. BAL 9, a lymphoma of the Lyt-1+,2+ T cell phenotype, was the most sensitive to DCF in vivo, and its DNA synthesis was inhibited more than 95% when cultured in the presence of dAr and DCF in vitro. This was correlated with a 10-fold increase in dATP content. The ADA and AMPDA activities were both high. Two lymphomas of the Lyt-1-,2+ T cell phenotype, BAL 5 and AKTB - lt , as well as two B cell phenotype lymphomas, A20 .3 and AKTB -lb, were all moderately inhibited in their in vivo growth if enough DCF was administered. However, their DNA synthesis in vitro was only inhibited 8 to 24% by dAr and DCF, there was only a twofold increase in the accumulation of dATP, and ADA and AMPDA activities were both low in the two BALB/c lymphomas tested. BAL 13, the only lymphoma of the Lyt-1+,2- phenotype examined, was completely resistant to DCF in vivo and in vitro. When cultured in the presence of dAr and DCF there was a transient increase in dATP content, followed by an abrupt decline. AMPDA activity was five to seven times greater than in the other lymphomas tested. ADA activity was moderate. The activities of 5' nucleotidase and of adenosine kinase were low and approximately equal in all the BALB/c lymphomas. These results suggest that the response to DCF by lymphomas of various immunologic phenotypes can be correlated with their nucleoside metabolism. The sensitivity of BAL 9 and the resistance of BAL 13 to DCF are correlated with their tendency to accumulate dATP and with their AMPDA and ADA activity ratios. The moderate sensitivity to DCF in vivo of the other T and B cell lymphomas, however, could not be clearly explained by any of the in vitro parameters thus far investigated, and this suggests that mechanisms inhibiting lymphoma proliferation other than dATP accumulation may be operating.