The aim of this study is to compare effectiveness and safety of Infliximab (INF), Etanercept (ETN), and Adalimumab (ADA) in patients with psoriatic arthritis (PsA) with inadequate response to a previous disease-modifying antirheumatic drug (DMARD). One hundred consecutive PsA patients with inadequate response to a previous DMARD entered this study. Clinical and laboratory assessment at baseline (T0) and 12 (T12) months were performed and included physical examination, vital signs, global Psoriasis Area and Severity Index (PASI; extension of psoriasis), tender joints count (TJC), swollen joint count, health assessment questionnaire (HAQ; questionnaire for measuring disability), and monitoring of adverse events (AEs). After enrollment, all patients were randomly given INF 5 mg/Kg every 6-8 weeks, ETN 50 mg weekly, or ADA 40 mg every other week. Baseline therapy with DMARD remained unchanged. Effectiveness was defined as percentage of ACR20 responders and as clinical remission and/or minimal disease activity at 12 months treatment. INF, ETN, and ADA all effectively controlled signs and symptoms of PsA. All variables tested showed at T12 for each treatment a significant variation from the baseline value. In particular, patients on INF and ADA showed the greatest improvement in terms of PASI, while patients on ETN showed the greatest improvement on TJC and HAQ. ACR response rates were 72% of patients on ETN, 70% of those on ADA, and 75% of those patients on INF. Occurrence of AEs was reported in 15% of the cases. Only two AEs in patients on INF were considered drug related, pneumonitis and thrombocytopenia, respectively. All tumor necrosis factor-alpha blockers significantly controlled signs and symptoms of PsA. An increased knowledge of the different profiles of these agents may help in optimizing their use.