This paper presents the first CMOS Vascular Endothelial Growth Factor (VEGF) sensor for cancer diagnosis directly from human blood. The sensor incorporates a peptide aptamer-based microneedle that allows the detection of electrochemical reactions with VEGF. This results in a capacitance change between the microneedles and then reads out by a two-step capacitance-to-digital converter (CDC). The proposed two-step CDC consists of a coarse 5b slope ADC and a fine 14b continuous-time delta-sigma modulator (CTDSM). During slow peptide-binding, the slope ADC performs a coarse conversion and the results are used to adjust the current level of the stimulator. After settling of the peptide-binding, based on an adjusted stimulation current, the CTDSM measures the small capacitance changes of the sensor. The prototype chip is fabricated in a 65-nm CMOS process, occupying a 0.87 mm2 active area. The power consumption is 270 W. Thanks to the two-step approach, this work achieves a wide dynamic range of 18.3b, covering a large sensor-to-sensor variation. It also achieves a peak resolution of 13.7b, while maintaining <0.02% errors in 1 to 100 nF baseline capacitance. The overall sensor system successfully detects the VEGF in both phosphate-buffered saline (PBS) and human blood serum. Without the use of precision instruments, this work achieves a resolution of 15 fMrms in range of 0.1 to 1000 pM and denotes the clear VEGF selectivity at 40× in PBS and 5× in the blood serum compared to other proteins (IgG, Con A, and cholera toxin).