Nanogenerators were first demonstrated by deflecting aligned ZnO nanowires using a conductive atomic force microscopy (AFM) tip. The output of a nanogenerator is affected by three parameters: tip normal force, tip scanning speed, and tip abrasion. In this work, systematic experimental studies have been carried out to examine the combined effects of these three parameters on the output, using statistical design of experiments. A statistical model has been built to analyze the data and predict the optimal parameter settings. For an AFM tip of cone angle 70° coated with Pt, and ZnO nanowires with a diameter of 50 nm and lengths of 600 nm to 1 μm, the optimized parameters for the nanogenerator were found to be a normal force of 137 nN and scanning speed of 40 μm/s, rather than the conventional settings of 120 nN for the normal force and 30 μm/s for the scanning speed. A nanogenerator with the optimized settings has three times the average output voltage of one with the conventional settings. © 2010 Tsinghua University Press and Springer-Verlag Berlin Heidelberg.