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In continuation of efforts to correlate the antitemplate activities of modified polynucleotides with their structure, and to understand the factors governing both their potency and stability, a group of single-stranded poly(ribo- and deoxyribo-) nucleotides, and the "hybrid" double-stranded complexes were prepared and investigated. The double-stranded hybrid poly(A,hs5U).poly(dT) section was found to be more stable to murine blood nucleases than was the single-stranded poly(A,hs5U). In a comparative study as inhibitors of the DNA polymerase alpha from rat hepatoma, the results showed that the modified polynucleotides were more potent than the unmodified ones, in general, the polydeoxyribonucleotides were better antitemplates than their ribo counterparts and the poly(A70,hs5U30).poly(dT) hybrid was more active than either of the single-stranded components. Thus it is possible to increase the nuclease resistance of the modified polyribonucleotides by forming hybrid complexes with complementary polydeoxyribonucleotides, and at the same time, to augment their antitemplate activities.