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Immunotherapies and targeted therapies have shown significant benefits for melanoma survival in the clinical trial setting. Much less is known about the characteristics and associated outcomes of those receiving such therapies in real-world settings. This study describes the characteristics of patients with advanced melanoma receiving immuno- and/or targeted therapies in a real-world setting. This prospective cohort study enrolled participants aged >18 years, diagnosed with advanced melanoma and currently undergoing immuno- and/or targeted therapies outside a clinical trial for follow-up with three-dimensional (3D) total-body imaging. Participants (n = 41) had a mean age of 62 years (range 29–86), 26 (63%) were male and the majority (n = 26, 63%) had ≥2 comorbidities. After a median of 39 months (range 1–52) follow-up, 59% (n = 24/41) of participants were alive. Despite multiple co-morbidities, the survival of participants with advanced melanoma treated using immuno- and/or targeted therapies was similar or better in our real-world setting compared to those treated in clinical trials using similar therapies. Larger studies powered to evaluate phenotypic and socio-economic characteristics, as well as specific comorbidities associated with survival in a real-world setting, are required to help determine those who will most benefit from immuno- and/or targeted therapies.