This paper presents the project, optimization, design details, and fabrication of an optical chemical sensor based on a Mach-Zehnder interferometer (MZI), fabricated with metal-oxide semiconductor compatible processes and materials. The sensing material is hexamethyldissilazane (HMDS) plasma polymerized thin film, which exhibits hydrophobic characteristics, high resistance to acid or basic solution, and adsorption of polar and nonpolar organic compounds. Both reference and sensor arms of the fabricated MZIs are covered with HMDS thin film in order to keep the device balanced. Different substances, such as water, 2-propanol, and hexane vapors are investigated. The high sensitivity of the MZI structure, associated with refractive index variations of about 10−4, paves the way for a myriad of sensor applications, such as humidity, organic compounds, proteins, antibodies (antigens), enzymes, pesticides, and others. The minimum detectable measurements were 4.6 mg/min for n-hexane and 0.2 mg/min for 2-propanol.