Aim. Not all maintenance patients respond to methadone in the same manner, and many complain of withdrawal symptoms during the 24-hour inter-dosing interval (i.e. the dose does not ‘hold’). The persistence of these complaints are a source of concern as they may signal unsanctioned drug use and poor treatment outcome. This study examined the prevalence and profile of symptom complaints in methadone maintenance patients who report that their methadone dose does not ‘hold’. Design. In the first phase, a cross-sectional survey of 114 methadone patients examined a range of symptoms including direct opioid effects, and withdrawal. Phase 2 involved a comparison of the temporal pattern of symptom complaints between patients who reported the oral dose not ‘holding’ and those who did not. Setting. Participants in this study were enrolled in the South Australian Public Methadone Maintenance Program. Measurements. In Phase I, a checklist of 21 commonly reported symptom complaints associated with methadone maintenance treatment was administered. In Phase 2, this checklist was modified to include only those symptoms that changed in the 24-hour inter-dosing interval. The checklist was administered eight times over this period. Further data were collected using the Morphine Benzedrine Group Scale of the Addiction Research Centre Inventory, a measure of positive opioid effect. Findings. In Phase 1, it was found that approximately one-third of the sample reported that the methadone dose was consistently inadequate in preventing withdrawal symptoms for the entire inter-dosing interval. They could not be differentiated by demographic, health, other drug use or treatment characteristics. In Phase 2, despite having a higher oral methadone dose, patients reporting that their daily dose did not ‘hold’ experienced a smaller degree of opioid effect, and a greater intensity of opioid withdrawal, during the 24-hour period. Conclusion. These data demonstrate that there is a change in pharmacodynamic response over the 24-hour period for all methadone patients, but the degree of change is greater in a subgroup of patients. Charting symptom presentation throughout the inter-dosing interval can aid in identifying those patients who are experiencing difficulties with their treatment regime.