The aim of this study was to design a new one step conjugation of monoclonal antibodies (MAbs) to surface activated pegylated polyester nanoparticles (NPs) and evaluate the pharmacokinetic profile and therapeutic effect of paclitaxel palmitate (pcpl) loaded anti-HER2 immunoNPs in mice as compared to pcpl solution and NPs following IV injection. The density of the antibody conjugated to the NPs was found to be around 35 MAbs/NP (70% coupling efficiency). In vitro cell culture studies showed good binding and uptake results when immunoNPs were incubated with PC-3 and CAPAN-1 cell lines. Both pcpl NPs and immunoNPs showed significant increased t1/2, C(max) and AUC values as compared to the values of pcpl solution in mice. There was no significant difference in the C(max) and AUC values between pcpl NPs and pcpl immunoNPs. However, the immunoNPs concentrated much less in the liver and spleen than NPs. The pharmacokinetic behavior of the immunoNPs was markedly different from the pharmacokinetic profile of the naked MAb showing that the MAb lost its intrinsic molecular pharmacokinetic properties following conjugation to the NPs. The immunoNPs elicited a significant anti-tumor activity as compared to the pcpl solution and NPs, although the tumor growth was not fully inhibited.