Although allergic drug reactions have been considered to be immediate (IgE mediated) or delayed (T-cell effector mechanisms), accelerated reactions have also been defined; however, they have not been sufficiently studied. To study the mechanisms involved in accelerated reactions to amoxicillin. We monitored the response in 3 patients who had an accelerated reaction to amoxicillin. A T-cell effector response was searched after a Drug Provocation Test. Symptoms were recorded after initiation of the reaction, and sequential samples were taken at different intervals after challenge. Skin biopsy specimens were also taken, and a lymphocyte transformation test (LTT) was performed. After the drug provocation test, all 3 patients had a positive response within 2 to 6 hours of drug administration, with full expression at 6 hours, requiring corticoids and antihistamine treatment. They had generalized erythema with facial angioedema but no cardiovascular or respiratory symptoms. Monitoring of the response revealed the presence in the skin of CD4 and CD8 lymphocytes with increased expression of homing and cell activation markers. Immunohistochemistry revealed a perivascular mononuclear cell infiltrate with activated CD4 and CD8 cells expressing perforin and granzyme B. No tryptase release was detected in either the affected tissue or the peripheral blood. The LTT result was positive in all 3 patients. We found that accelerated reactions to β-lactams are mediated by effector T cells. The increase in different T-cell markers and a positive LTT result to amoxicillin, in parallel with the occurrence of symptoms after challenge, support this mechanism.