Abstract Carbon nanotubes have shown great potential in various areas of biomedicine. Herein, we synthesize a series of amphiphilic polymers by anchoring polyethylene glycol (PEG) of different lengths at various densities on poly(maleic anhydride-alt-1-octadecene) (PMHC18 ). The blood circulation and biodistribution of those PEG-PMHC18 -coated SWNTs in mice after intravenous injection are measured by an established Raman spectroscopy method. It is found that heavily PEGylated SWNTs with ultra-long blood circulation half-lives, although shows high uptake in the tumor, tend to accumulate in the skin dermis. A surface coating which affords SWNTs a blood half-life of 12–13 h appears to be optimal to balance the tumor-to-normal organ (T/N) uptake ratios of nanotubes in major organs. Using the selected SWNT conjugate, we then carry out a pilot in vivo photothermal therapy study and observe a promising cancer treatment efficacy. Our results highlight the importance of surface coating to the in vivo behaviors of nanomaterials in general and could provide guidelines to the future design of SWNT bioconjugates for various in vivo applications.