Cotton balls are used in neurosurgical procedures to assist with hemostasis and improve vision within the operative field. Although the surgeon can reshape pieces of cotton for multiple intraoperative uses, this customizability and scale also places them at perpetual risk of being lost, as blood-soaked cotton balls are visually similar to raw brain tissue. Retained surgical cotton can induce potentially life-threatening immunologic responses, impair postoperative imaging, lead to a textiloma or misdiagnosis, and/or require reoperation. This study investigated three imaging modalities (optical, acoustic, and radiographic) to find the most effective method of identifying foreign bodies during neurosurgery. First, we examined the use of dyes to increase contrast between cotton and surrounding parenchyma (optical approach). Second, we explored the ability to distinguish surgical cotton on or below the tissue surface from brain parenchyma using ultrasound imaging (acoustic approach). Lastly, we analyzed the ability of radiography to differentiate between brain parenchyma and cotton. Our preliminary testing demonstrated that dark-colored cotton is significantly more identifiable than white cotton on the surface level. Additional testing revealed that cotton has noticeable different acoustic characteristics (eg, speed of sound, absorption) from neural tissue, allowing for enhanced contrast in applied ultrasound imaging. Radiography, however, did not present sufficient contrast, demanding further examination. These solutions have the potential to significantly reduce the possibility of intraoperative cotton retention both on and below the surface of the brain, while still providing surgeons with traditional cotton material properties without affecting the surgical workflow.