Lateralized periodic discharges (LPDs) are commonly seen on EEG in critically ill patients. They are often associated with seizures, but some patients may have them without seizures. Therefore, they are considered to lie in the ictal-interictal continuum. When ictal, they require multiple antiepileptic drugs to treat effectively, which can expose the patient to iatrogenic complications. Therefore, optimal management is controversial. We present here two cases where perfusion-weighted MRI was useful in distinguishing ictal from interictal LPDs. In the first patient, hyperperfusion in the area showing LPDs was considered an indication that the LPDs were ictal, and aggressive treatment led to clinical improvement. The second patient had no asymmetry on perfusion-weighted MRI, and therefore, we did not escalate antiepileptic therapy, and the LPDs resolved spontaneously over the next few days. Perfusion-weighted MRI offers several advantages over other techniques, such as single-photon emission computerized tomography that have been used for this purpose before. It does not expose the patient to radiation, and newer techniques like arterial spin labeling can even obviate the need for intravenous contrast. Larger scale studies using perfusion-weighted MRI will be of great value to clinical practice.