Recent findings indicate that the hippocampus supports not only longterm memory encoding but also plays a role in working memory (WM) maintenance of multiple items; however, the neural mechanism underlying multi-item maintenance is still unclear. Theoretical work suggests that multiple items are being maintained by neural assemblies synchronized in the gamma frequency range (25-100 Hz) that are locked to consecutive phase ranges of oscillatory activity in the theta frequency range (4-8 Hz). Indeed, cross-frequency coupling of the amplitude of high-frequency activity to the phase of slower oscillations has been described both in animals and in humans, but has never been linked to a theoretical model of a cognitive process. Here we used intracranial EEG recordings in human epilepsy patients to test pivotal predictions from theoretical work. First, we show that simultaneous maintenance of multiple items in WM is accompanied by cross-frequency coupling of oscillatory activity in the hippocampus, which is recruited during multiitem WM. Second, maintenance of an increasing number of items is associated with modulation of beta/gamma amplitude with theta band activity of lower frequency, consistent with the idea that longer cycles are required for an increased number of representations by gamma cycles. This effect cannot be explained by a difference in theta or beta/ gamma power. Third, we describe how the precision of cross-frequency coupling predicts individual WM performance. These data support the idea that working memory in humans depends on a neural code using phase information. W orking memory (WM), the ability to maintain information about multiple items over a short time span, is indispensable for goal-directed behavior (1). Precise synchronization of neurons and neural networks results in oscillatory activity patterns in the gamma frequency range (25-100 Hz) and serves to facilitate neural communication and memory processing (2, 3). Data from animals and humans provide evidence that sustained increases of high-frequency activity (4-7) and theta (4-8 Hz) oscillations (8-10) are a neural correlate of WM maintenance. However, how multiple items can be simultaneously maintained without interference remains unknown. In animals, action potentials firing with respect to specific phases of ongoing theta oscillations accompany the encoding of sequences of spatial positions (11). In addition, firing rate is modulated by the phase of gamma band activity (12, 13). A related phase code based on interactions of theta phase and gamma oscillations has been suggested to support maintenance of multiple items in WM (14,15). Such crossfrequency coupling has been described in rodents (16,17) and recently in the human brain (18,19), but its link to multi-item WM has not been investigated.Here we address the question of whether multiple items are encoded by modulation of the amplitude of high-frequency oscillations by the phase of oscillations in a lower-frequency range in the human hippocampus. We used a modified Sternberg paradigm...