The molecular basis of many health outcomes attributed to solar ultraviolet radiation (UVR) is unknown. We tested the hypothesis that they may originate from transcriptional changes in blood cells. This was determined by assessing the effect of fluorescent solar simulated radiation (FSSR) on the transcriptional profile of peripheral blood pre- and 6h, 24h and 48h post-exposure in nine healthy volunteers. Expression of 20 genes was down-regulated and one was up-regulated at 6h after FSSR. All recovered to baseline expression at 24h or 48h. These genes have been associated with immune regulation, cancer and blood pressure; health effects attributed to vitamin D via solar UVR exposure. Plasma vitamin D3 [25(OH)D3] levels increased over time after FSSR and were maximal at 48h. The increase was more pronounced in participants with low basal 25(OH)D3 levels. Mediation analyses suggested that changes in gene expression due to FSSR were independent of 25(OH)D3 and blood cell subpopulations.