The deployment of downhole packers in Electrical Submersible Pump (ESP) completions brings many added benefits to the wellbore integrity, yet it adds a certain degree of complexity to the completion design, installation, and operation. Thermal expansion of the trapped completion fluid in the tubing-casing-annulus (TCA), located between the ESP upper completion packer and the tubing hanger, poses several risks to the wellbore integrity, including tubing collapse, wellhead rupture, packer failure, casing failure, ESP cable failure, and packer electric penetrator failure. The increase in TCA pressure is accelerated in ESP wells because of their capability to instantaneously produce high volumes of hot reservoir fluids to the surface. Improper bleeding of TCA pressure results in explosive decompression (ED) of the different ESP cable components leading to a sudden premature failure of the electrical system. While appropriate bleed-off procedures have shown to minimize ED effects the selection of suitable ESP cable materials have eliminated these types of TCA cable failures. Gathering data from multiple sources such as Dismantle Inspection and Failure Analysis (DIFA), ESP downhole sensors, laboratory tests, and completion pull reports was a critical step for accurate identification of the root cause behind the encountered TCA problems. The followed analysis methodology showed that selection of packer elastomers that are suitable for the reservoir conditions was proven to be of extreme importance to the wellbore integrity and the ESP runlife. In the presented case study, changing to high-grade elastomer packers was necessary in order to tolerate the high hydrogen sulfide (H2S) partial pressure experienced in the studied field. Moreover, data gathered from DIFA proved that proper well cleanouts prior to ESP installation is also crucial in preventing explosive decompression of packer penetrator. In fact, effective TCA management is an important strategy that needs to be implemented in both the design and operation of the well completion.