Background:Hydrochlorothiazide (HCTZ) is a commonly used thiazide diuretic prescribed to treat hypertension and fluid retention. While effective and generally well-tolerated, long-term use has been associated with an increased risk of cutaneous squamous cell carcinoma (SCC), potentially due to its photosensitizing effects. SCC, a prevalent non-melanoma skin cancer, is influenced by UV exposure and is more likely to develop in immunocompromised individuals, such as kidney transplant recipients—many of whom are prescribed HCTZ. Objective:To investigate the association between HCTZ use and the incidence of SCC in kidney transplant recipients, with a focus on demographic variables. Methods:A retrospective cohort analysis was performed using the TriNetX research platform. Kidney transplant patients were divided into two matched cohorts based on HCTZ exposure. SCC incidence was compared between the groups. Results:Incidence and prevalence of SCC remained low in patients under 65 but increased sharply with age, peaking in the 75–79 group before declining in older cohorts. Native Hawaiian or Other Pacific Islander individuals had the highest incidence proportion, while Black and American Indian or Alaska Native groups had the lowest. Minimal sex-based differences were observed, and incidence was slightly higher among non-Hispanic patients compared to Hispanic individuals. Discussion:This study underscores the increased risk of SCC in immunocompromised populations prescribed HCTZ. Notably, demographic factors such as race, sex, and age remain underrepresented in existing literature, yet are crucial for understanding individual risk profiles. Conclusion:HCTZ use in kidney transplant recipients may elevate SCC risk. Personalized risk assessment should be considered when prescribing HCTZ in this vulnerable population.