Erythema multiforme major (EMM) is an acute, self-limited mucocutaneous disease characterized by the abrupt onset of symmetrical fixed red papules evolving to target lesions. It is triggered mainly by infections, such as herpes simplex virus (HSV) and Mycoplasma pneumoniae, or drugs. In instances of extensive skin lesions with "giant" targets, prominent involvement of several mucous sites and fever, it may be difficult to distinguish from Stevens-Johnson syndrome (SJS), a rarer, life-threatening reaction which is mainly drug-induced. We report a 7-year old boy with SJS and Chlamydia pneumoniae infection and 3 patients with erythema multiforme (EM) and co-infection with Chlamydia pneumoniae: a 3-year old girl and a 29-year old man developed EMM lesions associated to Mycoplasma pneumoniae and Chlamydia pneumonia and a 20-year old woman with EMM associated to herpes simplex type 2 and Chlamydia pneumoniae infection. None of the 4 patients had history of drug intake in the last two months. Chlamydia pneumoniae is an intracellular bacteria responsible for respiratory infections. Despite the fact that its role in SJS/EMM has been rarely reported, our cases suggest that it may cause SJS and trigger EM when co-infecting a patient, either with Mycoplasma pneumoniae or herpes simplex. We conclude that infection by Chlamydia pneumoniae should be suspected and ruled out in every patient with SJS/EMM, especially in those with signs of respiratory infection.