Apo (a) is a very atherogenic plasma protein without apparent function, which is highly expressed in humans. The variation in plasma Lp (a) concentration among individuals is considerable. Approximately 10–15% of the white population exhibit plasma Lp (a) concentrations above the atherogenic cut-off value of approximately 30 mg/dl. Since there is currently no safe way of treating those patients with drugs, we have tested the possibility of interfering with apo (a) biosynthesis by adenovirus-mediated expression of antisense apo (a) mRNA comprising the 5′ UTR, the signal sequence and the first three kringles of native apo (a). Transduction of rat hepatoma McA RH 7777 cells which stably expressed apo (a) with 18 kringle IV (KIV) domains with apo (a)-antisense adenovirus (AS-Ad) at multiplicity of infection (MOI) of 30 reduced apo (a) synthesis to 23% as compared with control cells. As apo (a) is not synthesized in laboratory animals, we induced biosynthesis of the N-terminal fragments of apo (a) in mice by adenovirus-mediated gene transfer. Cotransduction of these mice with AS-Ad, which expressed up to eight times higher amounts of apo (a) than stable transgenic apo (a) mice, led to an almost complete disappearance of apo (a) from plasma. We conclude that the proposed AS-construct is very efficient in interfering with apo (a) biosynthesis in vivo. The strategy of inducing the synthesis of a nonexpressed protein followed by knocking it out by AS technology may also be applicable to other systems.