Aim To evaluate factors associated with a negative outcome in a 3-year follow-up of subjects diagnosed with medication-overuse headache (MOH) (revised-ICHD-II criteria). Methods All consecutive patients entering the center’s inpatient detoxification program were analyzed in a prospective, non-randomized fashion. All participants were assessed by a neurologist using an ad hoc patient record form. Personality was assessed using the Minnesota Multiphasic Personality Inventory (MMPI)-2, Chi-square test, one-way analysis of variance (ANOVA), and odds ratios (OR) were calculated as appropriate. Results One-hundred and fifty patients completed the follow-up (79.3% females, age 46.40 ± 11.31 years): 13 never stopped their drug overuse (A), 38 stopped their overuse, but relapsed at least once (B), and 99 stopped and never relapsed (C). The Group A patients differed from those in B + C as they were more frequently single (OR 0.134; p = 0.007) and unemployed (OR 3.273; p = 0.04), took a higher number of drug doses ( p < 0.001), and less frequently drank coffee (OR 3.273; p = 0.044). Personality profile: subjects in A scored higher than those in C on the following scales: Hypochondriasis ( p = 0.007), Depression ( p = 0.003), Paranoia ( p = 0.025), Fears ( p = 0.003), Obsessiveness ( p = 0.026), Bizarre Mentation ( p = 0.046), Social Discomfort ( p = 0.004), Negative Treatment Indicators ( p = 0.040), Repression ( p = 0.007), Overcontrolled Hostility ( p = 0.040), Addiction Admission ( p = 0.021), Social Responsibility ( p = 0.039), and Marital Distress ( p = 0.028). Conclusion Disease outcome in MOH patients is influenced negatively by overuse severity and by specific psychological and socio-economic variables. Other possible modifier factors were voluptuary habits.