Tumor necrosis factor (TNF)-α plays a central role in psoriatic arthritis (PsA). A subgroup of patients with PsA do not respond to anti-TNF-α antibodies but respond to TNF receptor p75-Fc IgG fusion protein (etanercept), which also neutralizes lymphotoxin (LT)-α. It has been suggested that LT-α might be involved in the development of the disease. We determined LT-α serum levels in 15 PsA patients before (T0) and after 3, 6, 9, and 12 months of etanercept therapy (T3, T6, T9, and T12, respectively) and correlated them with their response to treatment. Bath Ankylosing Spondylitis Disease Activity Index, Psoriasis Area Severity Index, Disease Activity Score (DAS28), erythrocyte sedimentation rate (ESR), and C reactive protein (CRP) levels were assessed at the same time points. All patients showed a clinical response at T6, which persisted up to T12; ESR and CRP mean levels significantly decreased at T3 and remained within the normal range up to T12. LT-α levels significantly increased from T3 to T6 and returned to baseline levels at T12. Therefore, the LT-α serum levels do not seem to correlate with clinical and laboratory parameters of the response to etanercept in PsA patients. Further studies are required to better define the role of LT-α and LT-α blockade by etanercept in PsA patients.