SummaryBackground and ObjectivesPrevious work has demonstrated that hydrochlorothiazide (HCTZ) is a risk factor for squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) due to pro‐photocarcinogenic effects. Atypical fibroxanthoma (AFX) and pleomorphic sarcoma (PDS), both ultraviolet‐induced cancers, display a rare but rising cutaneous tumor entity. This study aimed to evaluate if the use of HCTZ is higher in patients with AFX/PDS than in patients with SCC/BCC and subsequently may be a risk factor for AFX/PDS‐development.Patients and MethodsIn a retrospective study of four German skin cancer centers, AFX/PDS cases and SCC/BCC controls were sex and age matched (1:3) over a time‐period of 7 years (2013–2019) to evaluate the use of HCTZ, immunosuppressive medication, second malignancies, and presence of diabetes mellitus.ResultsOverall, 146 AFX/PDS and 438 controls (SCC/BCC) were included in the study. The use of HCTZ was significantly higher in patients with AFX/PDS (44.5%) compared to patients with SCC/BCC (25.3%). Additionally, the presence of diabetes mellitus was significantly higher in AFX/PDS patients.ConclusionsThis study demonstrates a significantly higher use of HCTZ in patients with AFX/PDS compared to SCC/BCC. This result suggests that HCTZ may be a risk factor for AFX/PDS. Additionally, diabetes mellitus or its comorbidities may be associated with an increased risk for AFX/PDS.