Recombinant glycoprotein-deficient lymphocytic choriomeningitis virus-based vaccine vectors (rLCMV/ΔGP) are potent CD8(+) T cell inducers. To investigate the underlying molecular requirements, we generated a nucleoprotein-deficient vector counterpart (rLCMV/ΔNP). NP but not GP is a minimal trans-acting factor for viral transcription and genome replication. We found that, unlike rLCMV/ΔGP, rLCMV/ΔNP failed to elicit detectable CD8(+) T cell responses unless NP was trans complemented in a transgenic host. Hence, NP-dependent intracellular gene expression is essential for LCMV vector immunogenicity.