Beta-lactam antibiotics are a relatively common cause of immune thrombocytopenia. Because the many beta-lactam drugs now in clinical use have structural similarities, when a patient experiences this complication the question of whether an alternative member of this drug family can safely be used often arises but there are little data available to guide this decision. Drug-dependent, platelet-reactive antibodies from 32 patients who experienced thrombocytopenia while being treated with a beta-lactam drug of the penam (piperacillin, etc.) or cephem (ceftriaxone etc.) groups were studied for serologic cross-reactivity with other drugs from these families using flow cytometry. Cross-reactions observed were analyzed for correlations with structural features of the drugs tested. Among 14 antibodies specific for penam drugs, five "strong" cross-reactions with other penam drugs were found. Among 18 antibodies specific for cephem drugs, 8 "strong cross-reactions were identified. Antibodies induced by penam drugs did not cross-react strongly with cephem drugs and vice versa. A strong correlation between cross-reactions and similar or identical R1 side groups of the beta-lactams studied was observed. The findings suggest that patients who experience immune thrombocytopenia while being treated with a beta-lactam of the penam group can safely be treated with a cephem drug and vice versa. If a patient is to be switched to another beta lactam within the same group, the likelihood of serologic cross-reactivity can be minimized by choosing an agent with a distinctly different R1 side group.