Poly(ethylene glycol) (PEG) is widely applied to decorate nanocarriers due to its “long circulation” characteristics. However, the applications of linear PEG-modified nanocarriers have been hindered by severe adverse effects due to the accelerated blood clearance (ABC) phenomenon. It was universally known that anti-PEG antibodies (APAs) were main culprits in ABC phenomenon which induced the significant change in pharmacokinetics, biological distributions of the second injection and triggered complement activation-related pseudoallergies (CARPA). Recent studies have illustrated that APAs triggered the ABC phenomenon of PEGylated protein drug and even related to the CARPA of COVID-19 vaccine. Therefore, it is urgent to inhibit the generation of APAs and eliminate the ABC phenomenon. Here, “Y-type” PEG was chosen to replace linear PEG due to its weak immunogenicity. “Y-type” PEG-lipid derivatives [DSPE-mPEG_2,n (n = 2, 10, and 20 kDa)]-modified doxorubicin liposomes (DOX-PL_2,n) and topotecan liposomes (TP-PL_2,n) induced lower levels of APAs and could avoid activating complement system. In further research, we found that liposomes decorated with DSPE-mPEG_2,n could avoid the ABC phenomenon after duplicate injections. Furthermore, pharmacodynamic tests indicated that DOX-PL_2,n and TP-PL_2,n improved the curative effect of S180 tumor than DOX-PL_2k and TP-PL_2k (linear PEGylated liposomes). For the first time, DOX-PL_2,n and TP-PL_2,n were used for in vivo pharmacokinetic and pharmacodynamic experiments. Liposomes ornamented with “Y-type” PEG may provide new approaches to maintaining long blood circulation time, eliminating the ABC phenomenon of encapsulated active compounds, and also could weaken CARPA and improve tumor therapeutic effect. Our research aims to promote the research and development of “Y-type” PEG-decorated nanocarriers and provide a substantial academic basis for its clinical application.