We investigated whether topical brimonidine delayed or enhanced the development of squamous cell carcinoma (SCC) when ultraviolet radiation (UVR) was applied to a well-established murine model. Hairless female mice (n = 125) were randomized into five groups and treated as follows: 1% brimonidine cream before UVR (Group 1), 0.33% brimonidine gel before UVR (Group 2), 1% brimonidine cream after UVR (Group 3), UVR only (control; Group 4) and 1% brimonidine cream only (control; Group 5). For each animal, the first four tumors were recorded and followed until three tumors reached 4 mm or one tumor reached 12 mm in diameter. All animal experiments continued for up to 365 days or until death. Application of 1% brimonidine cream before UVR delayed tumor development relative to control mice treated with UVR alone (P = 0.000006). However, when 0.33% brimonidine gel was applied before UVR (P = 0.313) or 1% brimonidine cream was applied after UVR (P = 0.252), there was no significant delay in tumor development relative to control mice treated with UVR alone. The development of the second and third tumors followed a similar pattern. Topical 1% brimonidine cream applied before UVR exposure delayed SCC development in hairless mice. In contrast, when brimonidine was applied after UVR there was no significant delay in tumor development. These results suggest that the 1% brimonidine cream probably absorbed the UVR, and therefore, a delay in tumor formation was only seen when brimonidine was applied before irradiation. However, there can be multiple reasons for this delay in photocarcinogenesis.