Erythema nodosum (EN) is the most common type of septal panniculitis which causes inflammation of the subcutaneous fat, being the result of a hypersensitivity reaction to specific triggers. It usually presents with erythematous painful rounded lumps symmetrically on the anterior surface of the lower limbs. Rarely, it may occur in other areas such as thighs, neck and arms. This is a retrospective study describing a cohort of patients hospitalized in the University Hospital of Heraklion, Heraklion, Greece. The present research compares characteristics between patients with and without relapse and identifies independent factors associated with relapse. All patients with EN hospitalized during a 17-year period were included. Data regarding epidemiology, current or recent infections, symptoms, laboratory values and relapses were all recorded and evaluated. In total, 138 patients, of which 27 (19.6%) males, with a median age of 46.5 years, were evaluated. Clinical presentation involved multiple lesions in 115 (83.3%) patients, while 12 (8.7%) of them were febrile. Relapse was noted in 27 (19.6%) subjects. Multivariate logistic regression analysis showed that male gender was associated with a higher risk of relapse, while cases with multiple lesions were associated with a lower risk.