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Liposomes with peptides motifs have been widely applied for targeted delivery of anticancer drugs. However, few studies have questioned whether peptide modification on liposomes may induce serious toxicity associated with immune stimulation. Here, we report that display of a tumor targeting cyclic RGD peptide (e.g. c(RGDyK) and c(RGDfK) on the surface of liposomes can be a potent inducer of lethal hypersensitivity-like reactions in mice upon re-administration, with the main symptom a sudden drop in body temperature. The hypothermia usually abates within 4 h but is sometimes lethal with death happening within 30 min post injection. This reaction has been proven to be IgE-independent acute systemic anaphylaxis, which may due to IgG immune complex triggered complement activation, anaphylatoxin and cytokine release, etc., leading to acute conspicuous organ damage. Results from an exploration of influence factors showed that the immunotoxicity of c(RGDyK)-liposomes could not be eliminated by minimizing the c(RGDyK) motif ratio, or by decreasing injection doses in the normal dose range, or by increasing the mPEG-DSPE motif ratio. However, encapsulation of a strong cytotoxic drug completely shut off this unwanted immune response. Investigation with a series of peptides containing the RGD sequence suggested that the lethal immunotoxicity of the cyclic RGD peptide was RGD sequence and peptide cyclization dependent. This study provides a valuable alert for the utilization of peptide modified liposomes in drug delivery, especially when carrying low-toxicity drugs.