Synthetic peptides of the herpes simplex virus glycoprotein B synthesized either as a free form or derivatized with one (PAM1) or three palmitic acids (PAM3Cys) were used to assess the in vivo priming efficacy of high affinity virus-specific CTL induction. The peptide and its derivatives were delivered in vivo with or without liposome encapsulation. Neither the free peptide nor the PAM1 derivative primed for high affinity virus specific CD8+ CTL induction, whether delivered via liposomes or not. On the other hand, the PAM3Cys derivative was able to prime for low levels of high affinity virus specific CD8+ CTL induction in the absence of liposome encapsulation. However, the efficiency of virus-specific CD8+ CTL induction with PAM3Cys derivative was enhanced following encapsulation in the liposomes. In contrast, all forms of the peptides induced both CD4+ T cell proliferative response as well as high affinity virus-specific CD4+ CTL. In addition, the efficiency of the PAM3Cys derivative to prime for CD4+ or CD8+ CTL was found to be influenced by the liposome encapsulation. When delivered via liposomes, the PAM3Cys derivative effectively primed for CD8+ CTL. However, liposomal delivery was not necessary for efficient priming for CD4+ CTL induction. Thus, both the acylation units as well as liposomal delivery appear to influence the in vivo priming of CD4+ and CD8+ T cell responses with synthetic peptides.