Background: Little is known about the prevalence and clinical significance of heterogeneity of positron emission tomography with 18F-labelled fluorodeoxyglucose-positron emission tomography (FDG-PET) response. We aim to determine the prevalence, and clinicopathologic correlates of intra-patient heterogeneity of FDG-PET response in metastatic melanoma treated with dabrafenib, and to determine whether heterogeneity predicts clinical outcome. Methods: Patients with BRAF mutant metastatic melanoma and ≥2 FDG avid lesions treated on the Phase I trial of dabrafenib at a single institution (n = 23) were included. FDG-PET response was assessed by comparing baseline PET scans with scans at day 15. A heterogeneous response was defined as responding and new or metabolically progressing lesion(s) in a patient, or >10% of lesions with a stable metabolic response and responding lesions in a patient. Results: Six (26%) patients had a heterogeneous PET response. The median time to progression (TTP) was 7.4 months (95% confidence interval (CI): 6.5-8.3) for PET homogeneous responders and 3.0 months (95% CI: 0.6-5.4) for PET heterogeneous responders. There were no homogeneous non-responders. Age, BRAF mutation genotype, dose, and lactate dehydrogenase, did not predict for heterogeneity of PET response. Heterogeneity did not correlate with tumour response. Lung metastases were more likely to respond than other visceral metastatic sites. Conclusions: Heterogeneous FDG-PET responses are common in metastatic melanoma treated with dabrafenib, and heterogeneity is associated with a shorter TTP. FDG-PET heterogeneity may predict molecular heterogeneity, and FDG-PET directed biopsies may facilitate investigation into mechanisms of resistance to signal pathway inhibitors.