Ball-in-shell structured TiO2 nanospheres were successfully made by flame synthesis-a single-step, continuous, and scalable process. The morphology and structure were systematically characterized by X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analysis, transmission electron microscopy, scanning electron microscopy, and N-2 sorption. TiO2 nanostructures with good crystalline nature and thermal stability were formed by feeding a titanium tetrachloride and alcohol vapor mixture to a facile diffusion flame. The resultant ball-in-shell spheres were composed of nanocrystallites, with shell thickness and void space width of 30-50 nm and 10-30 nm, respectively. The formation mechanism of ball-in-shell spheres was investigated, depending on the competition between the chemical reaction rate and diffusion rate during the flame process. Furthermore, UV-vis characterization indicates that this structure endows the spheres with higher light absorbance, which may be favorable to design and prepare novel materials with enhanced photocatalytic activities.