Purpose: Retinitis pigmentosa (RP) is a chronic progressive disease with no curative treatments. Understanding the variables involved with improving patients’ quality of life is important in managing this population. The literature investigating the relationship of anxiety and depression with RP relies on the analysis of smaller subset populations of patients with RP, and no study has quantified the effect size of the potential association. This study aims to elucidate and quantify the association between RP, anxiety, and depression. Methods: A retrospective case-control study was conducted of 6 093 833 medical records within the University of North Carolina Hospital and outpatient clinic system from July 1, 2004, to August 30, 2019. Patients with a diagnosis of RP, anxiety, and depression were identified within the Carolina Data Warehouse for Health by International Classification of Diseases, Ninth and Tenth Revision codes. Results: From the base population of 6 093 833 patients' medical records, 690 patients were diagnosed with RP, 253 065 with anxiety, and 232 541 with depression. Patients with RP have an odds ratio, adjusted for sex and age, of 4.915 (95% CI, 4.035-5.987) for having comorbid anxiety, 5.609 (95% CI, 4.622-6.807) for comorbid depression, and 4.130 (95% CI, 3.187-5.353) for comorbid anxiety and depression. Conclusions: Patients with RP have a higher prevalence of anxiety and depression, with increased odds of approximately 5 to 6 times for also carrying a diagnosis of anxiety or depression and about 4 times for carrying diagnoses of anxiety and depression compared with the general population.