Several antitumor agents known to bind DNA were complexed with this macromolecule and tested for activity against experimental animal tumor systems. Combination studies with these agents and DNA were carried out at the same time. Actinomycin D activity against the P388 lymphocytic leukemia in BALB/c X DBA/2 F1 mice was significantly potentiated by calf thymus DNA, both when complexed and when injected in combination. The DNA could be given as much as 4 hr before or after the antibiotic and still give potentiation. Synergism was also obtained when the DNA was autoclaved prior to complexing and/or injecting. Similarly, adriamycin activity against the L1210 lymphoid leukemia in DBA/2 mice was significantly potentiated by autoclaved herring sperm DNA, both as a complex and when injected in combination. When above-optimal levels of adriamycin were complexed with autoclaved herring sperm DNA and injected into BALB/c mice inoculated with the Madison 109 alveogenic carcinoma, the early lethality was delayed and antitumor activity was sometimes observed. Herring sperm DNA injected alone also had antitumor activity against the Madison 109 tumor. Similarly, activity was obtained against this tumor system with calf thymus DNA and actinomycin D when injected alone. In addition, DNA, in combination and when complexed with actinomycin, prevented the toxicity observed with BALB/c mice, inoculated with the Madison 109 tumor, were given injections of an above-optimal dose of this antibiotic.