Abstract Introduction Trimix, an intracavernosal injection therapy, is an effective treatment for erectile dysfunction. However, patient compliance with Trimix use is crucial for treatment success, and factors influencing compliance are not well understood. Objective This retrospective analysis aimed to identify factors that influence compliance with Trimix therapy among patients with erectile dysfunction. Additionally, the study aimed to investigate the impact of comorbidities, specifically diabetes and prostate cancer, on the duration of Trimix treatment. Methods Patient data from pharmacy records between 2017 and 2022 was analyzed. Custom Python code was used to calculate the duration of Trimix use based on the first and last prescription refill events. A comprehensive chart review was conducted to collect additional patient-related data, including demographics and comorbidities. Cox Proportional Hazards Regression models were employed to assess the effects of predictor variables on the duration of Trimix use. Simple linear regression was used to compare the presence of diabetes, prostate cancer, or both on time spent on Trimix treatment. Results The analysis included a total of 4,072 patients. Age was identified as a significant predictor of Trimix therapy discontinuation, with every additional year of age associated with an increased hazard ratio of 1.007 (p < 0.001). Preferred language also emerged as a significant predictor, with patients preferring Spanish exhibiting a higher hazard ratio of 1.163 compared to patients preferring English (p = 0.004). In terms of comorbidities, the presence of prostate cancer significantly differed from other organic causes of erectile dysfunction on time spent on Trimix treatment (p = 0.002), resulting in 80 fewer days of Trimix treatment. Conclusions This retrospective analysis revealed that age and preferred language are important factors influencing compliance with Trimix therapy. Older patients and those preferring Spanish were more likely to discontinue Trimix treatment. Additionally, the presence of prostate cancer significantly impacted the duration of Trimix treatment. These findings emphasize the need for age-specific counseling, language-concordant interventions, and tailored approaches to address comorbidities such as prostate cancer. Understanding these factors is vital for optimizing treatment adherence and efficacy in patients with erectile dysfunction. Disclosure No.