BACKGROUND: currently one of the major challenges facing clinical guidelines is multimorbidity. Current guidelines are not designed to consider the cumulative impact of treatment recommendations on people with several conditions, nor to allow comparison of relative benefits or risks. This is despite the fact that multimorbidity is a common phenomenon. OBJECTIVE: to examine the extent to which National Institute of Health and Clinical Excellence (NICE) guidelines address patient comorbidity, patient centred care and patient compliance to treatment recommendations. METHODS: five NICE clinical guidelines were selected for review (type-2 diabetes mellitus, secondary prevention for people with myocardial infarction, osteoarthritis, chronic obstructive pulmonary disease and depression) as these conditions are common causes of comorbidity and the guidelines had all been produced since 2007. Two authors extracted information from each full guideline and noted the extent to which the guidelines accounted for patient comorbidity, patient centred care and patient compliance. The cumulative recommended treatment, follow-up and self-care regime for two hypothetical patients were then created to illustrate the potential cumulative impact of applying single disease recommendations to people with multimorbidity. RESULTS: comorbidity and patient adherence were inconsistently accounted for in the guidelines, ranging from extensive discussion to none at all. Patient centred care was discussed in generic terms across the guidelines with limited disease-specific recommendations for clinicians. Explicitly following guideline recommendations for our two hypothetical patients would lead to a considerable treatment burden, even when recommendations were followed for mild to moderate conditions. In addition, the follow-up and self-care regime was complex potentially presenting problems for patient compliance. CONCLUSION: clinical guidelines have played an important role in improving healthcare for people with long-term conditions. However, in people with multimorbidity current guideline recommendations rapidly cumulate to drive polypharmacy, without providing guidance on how best to prioritise recommendations for individuals in whom treatment burden will sometimes be overwhelming.