Synthetic high-density lipoprotein nanoparticles (sHDL) are a valuable class of nanomedicines with established animal safety profile， clinical tolerability and therapeutic efficacy for cardiovascular applications. In this study we examined how the scavenger receptor B-I-mediated (SR-BI) tumor-targeting ability of sHDL， long plasma circulation half-life， and small particle size (9.6±0.2nm) impacted sHDL accumulation in SR-BI positive colorectal carcinoma cells， 3D tumor spheroids， and in vivo xenografts. We compared tumor accumulation of sHDL with that of liposomes (LIP， 130.7±0.8nm)， pegylated liposomes (PEG-LIP， 101±2nm)， and pegylated sHDL (12.1±0.1nm)， all prepared with the same lipid components. sHDL penetrated deep (210μm) into tumor spheroids and exhibited 12- and 3-fold higher in vivo solid tumor accumulation， compared with LIP (p<0.01) and PEG-LIP (p<0.05)， respectively. These results suggest that sHDL with established human safety possess promising intrinsic tumor-targeted properties.