In this retrospective study of institutionalized patients with mental retardation, we present the efficacy and safety of sequential treatment with intrarectal diazepam (IRD) gel (Diastat) and intravenous levetiracetam (IVL) in comparison with either treatment alone for acute repetitive or prolonged seizures (ARPS). We defined ARPS as >or=3 seizures of any type within 1 h or a single seizure of any type lasting >or=3 min. Eighty-eight ARPS episodes were treated in 25 patients (14 female, age 21-72 years), with mainly symptomatic generalized epilepsy. There were no adverse events directly attributable to the administration of IRD or IVL. Seizure recurrence within 4 h of treatment, the primary outcome measure, was significantly lower after combined sequential IRD + IVL treatment (3 of 36) compared to IRD alone (6 of 24, p = 0.048) or IVL alone (10 of 28, p = 0.039). There was no statistically significant difference between the individual IRD and IVL treatments (p = 0.604). The estimated odds ratio (OR) indicated that the risk of seizure recurrence was higher after IRD or IVL monotherapy compared to combined IRD + IVL treatment. Subsequent emergency room (ER) transfers following seizure recurrence were least likely after IVL treatment (10%) compared to combined IRD + IVL (67%) or IRD (83%) treatment. These findings suggest that although IRD or IVL monotherapy is efficacious, the combination is superior in controlling ARPS in this special group of institutionalized patients. In addition, we speculate that a more reliable onset of action after IVL treatment results in rapid seizure control and fewer ER transfers, despite seizure recurrence.