Efalizumab is an anti-CD11a humanized monoclonal antibody which is safe and effective for the treatment of plaque psoriasis. We performed a retrospective analysis on -high-need- patients with moderate-to-severe psoriasis treated with Efalizumab monotherapy for more than 2 years. Chart review of patient records also concerned information about rebound, relapse, and retreatment after temporary interruption, as well as transitioning from Efalizumab to alternative treatments. Of the 52 patients who completed the initial 12 weeks of treatment, 65% attained the PASI-50 response at week 12. A notable improvement of skin lesions on critical sites, such as palmoplantar surfaces or genitals, was also observed. Continuous treatment resulted in a sustained response in the majority of patients, with a PASI-75 response in nearly 88% of those Efalizumab-treated in the long term (week 72 onwards) and a PASI-90 in 77% of patients by weeks 120-132. In general, the treatment was well tolerated, with mild-to-moderate flu-like symptoms as the most frequent adverse events, particularly after the first two doses. Increase of leukocyte and/or lymphocyte counts was the most common laboratory test alteration during treatment, also in the long term. In our case series, Efalizumab was safe and well-tolerated even in patients with relevant comorbidities, including one patient with HBsAg carriage and five patients with latent TB.