Quantum dots (QDs) as luminescence probes play an important role in the field of life sciences and medicine in recent decades. However, hydrophobic QDs have many limitations in applications for biological imaging such as insolubility in aqueous solutions and nonspecific binding to cellular membranes and so on. This article describes the design and synthesis of d-alpha-tocopheryl polyethylene glycol 3350 succinate (TPGS(3350))-conjugated QDs (TPGS(3350)-QDs) nanoparticles (NPs) for effective reduction of nonspecific cellular binding of QDs for biological imaging. TPGS(3350) with n-poly(ethylene glycol) (PEG)(3350) group was used in order to enhance the stabilization and water solubility of QDs, and reduce nonspecific cellular binding of NPs with the function of long-chain PEG(3350). We have demonstrated that TPGS(3350)-QDs NPs show good stability and dispersion in aqueous solutions and that small amount of TPGS(3350)-QDs NPs were nonspecific bound with Michigan Cancer Foundation-7 (MCF-7) cells in comparison of mercaptoacetic acid-coated QDs NPs, which confirmed TPGS(3350) can efficiently reduce nonspecific cellular binding due to the effect of PEG(3350) in TPGS(3350). The nonspecific binding of TPGS(3350)-QDs NPs was also found to be much lower than that of TPGS-QDs NPs. The developed TPGS(3350)-QDs NPs in this study could be a promising tool for molecular imaging such as in vivo cell trafficking studies. (c) 2014 American Institute of Chemical Engineers AIChE J, 60: 1591-1597, 2014