Objective: To report a case of serum sickness–like reaction (SSLR) possibly induced by efalizumab, a recombinant humanized immunoglobulin G1 κ isotype monoclonal antibody approved for treatment of moderate-to-severe plaque psoriasis. Case Summary: A 37-year-old woman with plaque psoriasis who had been treated with efalizumab for 2 months developed a fever, erythematous rash, and progressive joint swelling and pain that required hospitalization. An exhaustive workup for infectious and rheumatologic causes of the patient's symptoms was negative. Given the relative temporal relationship between efalizumab therapy and the patient's signs and symptoms, a diagnosis of serum sickness was made. Systemic corticosteroids were initiated, which resulted in rapid resolution of the patient's signs and symptoms. Use of an objective causality assessment suggests that the patient's SSLR was possibly related to efalizumab. Discussion: Like many therapeutic monoclonal antibodies, efalizumab is associated with several adverse events, including allergic reactions. SSLR, a nonimmediate hypersensitivity syndrome, can occur with a variety of drugs including monoclonal antibodies. However, a MEDLINE search (1964–July 2008) identified only one other possible case of SSLR related to efalizumab. Conclusions: Clinicians using efalizumab should be aware of this possible adverse reaction.