Hydrochlorothiazide (HCTZ) is a frequently prescribed diuretic that exhibits photosensitizing properties. It is used to treat hypertension and edema. Dermato-epidemiological studies in various populations have linked HCTZ treatment with increased risk of particular types of skin cancer, including malignant melanoma (lentigo subtype), and both basal cell carcinoma and squamous cell carcinoma (SCC). This study investigated whether either of two different doses of HCTZ increased the risk of SCC development in mice exposed to ultraviolet radiation (UVR). A total of three groups of hairless mice were used in this study (total, N = 71). One group received a low dose (0.26 mg/mouse/day) and another group received a high dose (0.52 mg/mouse/day) of HCTZ in their drinking water; a third UVR control group received only tap water. All three groups were irradiated with UVR until the mice developed three tumours that were 4 mm in size. The times to SCC tumour development were recorded. In the low-dose group, the median time to develop an SCC tumour was 170 days; in both the high-dose group and the control group, the median time to develop anexd SCC tumour was 163 days (p ≥ 0.331). In our hairless mouse model, we found that mice treated with UVR plus HCTZ did not develop SCCs more rapidly than mice treated with UVR but not HCTZ.