New tools for monitoring response to primary melanoma treatment are needed to reduce recurrence rates and patient anxiety. A previously developed plasma-based microRNA signature (MEL38) was measured in four melanoma patient samples obtained before and 12-14 days after treatment (i.e. surgical excision), as well as in two nonmelanoma controls. The value of the MEL38 score and selected individual genes were compared between the time points. The MEL38 scores of the four patients with melanoma became more 'normal like' after tumour excision, with a statistically significant 15% mean reduction. MicroRNAs involved in tumour suppression were upregulated in the postexcision samples and those involved in facilitating treatment resistance and tumour invasion were downregulated. Based on these limited preliminary data, the MEL38 signature may have clinical utility in assessing an individual patient's response to the most common form of melanoma treatment. Additional studies are needed on larger, clinically diverse patient cohorts, sampled over longer periods of time.