Background Tumor necrosis factor-alpha (TNF-α) is pivotal in the pathogenesis of psoriasis, an immune-mediated disease. Adalimumab is a fully human, IgG1 monoclonal antibody that inhibits TNF-α. Objectives The aims of this study were to assess the efficacy and safety of adalimumab therapy for patients with moderate to severe plaque psoriasis and evaluate the duration of treatment response after withdrawal from or dosage reduction of adalimumab therapy. Methods In this multicenter, randomized, double-blind, placebo-controlled study, patients with moderate to severe plaque psoriasis received 12-week, open-label therapy with subcutaneous adalimumab, consisting of 80 mg of adalimumab at weeks 0 and 1, followed by 40 mg weekly at weeks 2–11. At week 12, patients who had an improvement in Psoriasis Area and Severity Index (PASI) score of ≥50% were randomized to blinded therapy and received either adalimumab 40 mg every other week (eow) or placebo for an additional 12 weeks. Results A total of 148 patients enrolled. Clinical response was rapid, with a PASI 50 response rate of 28% at week 2 of adalimumab therapy. At week 12, 91.9% (136/148) of patients had achieved ≥50% reduction in PASI (PASI 50) vs. baseline, 76.4% (113/148) had achieved PASI 75, and 47.3% (70/148) had achieved PASI 90. Of patients who were randomized to placebo at week 12, 30.9% (21/68) experienced a relapse (<PASI 50 improvement vs. baseline) by week 24, compared with 16.2% (11/68) of patients who received adalimumab 40 mg eow. In addition, 48.5% (33/68) of patients who were randomized to placebo at week 12 were PASI 75 responded at week 24, compared with 67.6% (46/68) of patients randomized to adalimumab 40 mg eow (p=0.032). And, 27.9% (19/68) of patients who were randomized to placebo at week 12 were PASI 90 responders at week 24, compared with 47.1% (32/68) of patients randomized to adalimumab 40 mg eow (p=0.028). Adalimumab was generally well-tolerated, and the rates of adverse events were comparable between the adalimumab and placebo groups. Conclusions Weekly adalimumab therapy rapidly improved psoriasis during an initial 12-week period. Improvement was sustained in most, but not all patients, despite dosage reduction to every other week. No patients randomized to adalimumab withdrawal (placebo at week 12) experienced rebound, and most maintained >PASI 50 improvement, relative to baseline, during the 3 months following adalimumab discontinuation. Overall, greater efficacy rates at week 24 were observed for patients randomized to continuous adalimumab therapy than for patients who were withdrawn from therapy at week 12.