Purified antibody to poly(adenylic acid)-poly(uridylic acid) was used in quantitative microcomplement fixation assays to detect conformational variations among several double-helical polyribonucleotide analogs of poly(adenylic acid)-poly(uridylic acid) or poly(inosinic acid)-poly(cytidylic acid) that had been previously evaluated for their ability to induce interferon. Modification at the furanose 2'-position of one or both strands resulted in a dramatic decrease in serological reactivity. Most modifications of the bases caused smaller serological changes, and no base modification caused complete loss of reactivity. The reaction patterns support the conclusion that the structure of the furanose and the overall conformation of the helix are critical in the formation of antigenic determinants. The backbones of both strands appear to be involved in forming a single antigenic site, and base modifications may alter the steric relationship between the backbones. In addition, the same structural changes that substantially alter recognition by antibody also lead to large changes in the interferon-inducing ability of the nucleic acid.