Liposomes are effective lipid nanoparticle drug delivery systems, which can also be functionalized with noninvasive multimodality imaging agents with each modality providing distinct information and having synergistic advantages in diagnosis, monitoring of disease treatment, and evaluation of liposomal drug pharmacokinetics. We designed and constructed a multifunctional theranostic liposomal drug delivery system, which integrated multimodality magnetic resonance (MR), near-infrared (NIR) fluorescent and nuclear imaging of liposomal drug delivery, and therapy monitoring and prediction. The premanufactured liposomes were composed of DSPC/cholesterol/Gd-DOTA-DSPE/DOTA-DSPE with the molar ratio of 39:35:25:1 and having ammonium sulfate/pH gradient. A lipidized NIR fluorescent tracer, IRDye-DSPE, was effectively postinserted into the premanufactured liposomes. Doxorubicin could be effectively postloaded into the multifunctional liposomes. The multifunctional doxorubicin-liposomes could also be stably radiolabeled with (99m)Tc or (64)Cu for single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging, respectively. MR images displayed the high-resolution micro-intratumoral distribution of the liposomes in squamous cell carcinoma of head and neck (SCCHN) tumor xenografts in nude rats after intratumoral injection. NIR fluorescent, SPECT, and PET images also clearly showed either the high intratumoral retention or distribution of the multifunctional liposomes. This multifunctional drug carrying liposome system is promising for disease theranostics allowing noninvasive multimodality NIR fluorescent, MR, SPECT, and PET imaging of their in vivo behavior and capitalizing on the inherent advantages of each modality.