Silicon nanowire field effect transistors (NWFETs) are low noise, low power, ultrasensitive biosensors that are highly amenable to integration. However, using NWFETs to achieve direct protein detection in physiological buffers such as blood serum remains difficult due to Debye screening, nonspecific binding, and stringent functionalization requirements. In this work, we performed an indirect sandwich immunoassay in serum combined with exponential DNA amplification and pH measurement by ultrasensitive NWFET sensors. Measurements of model cytokine interleukin-2 concentrations from <20 fM to >200 pM were demonstrated, surpassing the conventional NWFET urease-based readout. Our approach paves way for future development of universal, highly sensitive, miniaturized, and integrated nanoelectronic devices that can be applied to a wide variety of analytes.