Background Photodynamic therapy is an effective tool in the management of some forms of skin cancer and generalized solar dermopathy and can be beneficial in the management of acne vulgaris. When used as an area treatment one of the main limiters is the quite severe burning pain that patients feel during the illumination phase of the treatment. Objective To examine the effectiveness of a plant derived anti-nociceptive spray applied prior to and during large area photodynamic therapy. Methods A split face or left arm versus right arm, placebo controlled trial was performed on 60 patients to assess the effectiveness of the spray in reducing pain perception. Results There was a statistically significant reduction in pain at all illumination points during the illumination phase but no significant difference in discomfort levels in the first 72 h post illumination. Limitations Only large area photodynamic therapy treatment was performed during the study. No conclusions can be drawn for small area treatments. Conclusion Use of a simple, plant derived anti-nociceptive spray can reduce the discomfort experienced by patients undergoing photodynamic therapy to large areas.