This paper presents a novel auto-calibration technique for eliminating sensor mismatch in CMOS-based chemical imagers. Designed using an 8x8 array comprising of pH sensitive Ion Sensitive Field Effect Transistors (ISFETs), the chemical imager is capable of implementing a gradient based calibration algorithm by biasing programmable-gate (PG) ISFETs at a common operating point when exposed to a solution of homogenous pH. The system was fabricated in a typical 0.35um CMOS technology and demonstrated a fast rate of convergence (500ms per iteration) while a convergence accuracy of 45mV on a gain of 10 (0.5% relative standard error and 2% pixel-to-pixel variation) was achieved. A maximum pH sensitivity of 57mV/pH is also reported.