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This paper presents an extended model for the CMOS-based ion-sensitive field-effect transistor, incorporating design parameters associated with the physical geometry of the device. This can, for the first time, provide a good match between calculated and measured characteristics by taking into account the effects of nonidealities such as threshold voltage variation and sensor noise. The model is evaluated through a number of devices with varying design parameters (chemical sensing area and MOSFET dimensions) fabricated in a commercially available 0.35-μm CMOS technology. Threshold voltage, subthreshold slope, chemical sensitivity, drift, and noise were measured and compared with the simulated results. The first- and second-order effects are analyzed in detail, and it is shown that the sensors' performance was in agreement with the proposed model.