We explored the potential association of depression history and personality, evaluated through a robust questionnaire tool, namely the Eysenck Personality Scale, with disease risk and progression among Greek patients. A total of 106 melanoma patients and their 1 : 1 sex-matched controls were interviewed on the basis of a questionnaire comprising phenotypic, sociodemographic, lifestyle and medical history variables, as well as information on history of lifetime major depression. The Eysenck Personality Questionnaire, measuring the four personality dimensions (extraversion, neuroticism, psychoticism, lie), was thereafter completed. Adjusted odds ratios (ORs) for melanoma risk were derived through multiple logistic regression analyses, whereas potential predictors of survival were explored using Cox proportional hazards models. Sun sensitivity score [OR: 1.55, 95% confidence interval (CI): 1.16–2.06] and major depression history (OR: 5.72, 95% CI: 1.38–23.73) were significantly associated with melanoma, whereas inverse associations of extraversion (OR: 0.90, 95% CI: 0.83–0.97) and psychoticism score (OR: 0.88, 95% CI: 0.78–1.00) were noted. These associations were more pronounced and remained solely among female patients; notably, decreased extraversion (OR: 0.86, 95% CI: 0.76–0.98) and psychoticism score (OR: 0.63, 95% CI: 0.43–0.91), as well as increased depression history (OR: 10.69, 95% CI: 1.43–80.03) were evident. Cox-derived hazard ratios showed nonsignificant associations of depression history and personality with disease outcome. Our data support the hypotheses that depression history and personality are associated with melanoma risk. No effect on survival after cancer diagnosis was observed. If confirmed in future studies, these associations may contribute toward better understanding the etiology of melanoma, enhancing health-related quality of life.