Few objective data are available to answer this question, since the general tendency with drug trials is to evaluate singleagent interventions. Nonetheless, there is an evidence base to support certain combinations, and suggestions can be made by extrapolation from published studies with respect to others. The 5-aminosalicylates (5-ASA) are not themselves especially potent in Crohn’s disease (CD), and there are no clear signs that their addition to other agents proves beneficial. Topical 5-ASA in combination with oral 5-ASA is more effective than either alone in ulcerative colitis (UC), but data specific to CD do not exist. There is a modestly impressive evidence base in favor of antibiotics in active CD. They have not been formally assessed in combination with other agents, but there is an impression that patients perform better on the combination of metronidazole with ciprofloxacin than with either alone. No reliable data yet exist on the potential role of combining proor prebiotics either with antibiotics or with each other in CD. Steroids are increasingly avoided in CD other than in the acute situation. A recurring need for steroids is an indication for the introduction of immunomodulatory therapy. As many of these agents (especially azathioprine/6-mercaptopurine) take some weeks to become effective, it is obvious that the combination of steroid and immune agent will be employed during that induction time. It would, however, be wrong to consider this a true role of multiple drug therapy, as the immune agent is acting ultimately to replace the steroid, and not to complement it. Previous suggestions that coadministration of steroids with infliximab reduced the frequency of infusion reactions and other later complications have not been borne out. It is reasonable to provide bolus steroid (and antihistamine) at the time of infliximab infusion in those with previous reactions, but this is no longer appropriate as a routine. Combinations of conventional immunosuppressants are widely used in transplantation practice, in rheumatology, and in some other disease settings. The aims of using combinations include minimizing toxicity by using lower doses, while maximizing efficacy by combining complementary antiinflammatory effects. Good evidence exists to support these strategies. While apparently logical for CD, and supporting (for example) the use of low-dose azathioprine together with low-dose methotrexate, there are no supportive data. A retrospective study suggested that a combination of azathioprine and methotrexate was no better than methotrexate alone.1 Without better data, it would be ill-advised to adopt a combination strategy, since toxicities (especially on bone marrow) could prove to be additive. The combination of methotrexate with folic acid has been shown to improve net outcomes over and above those from methotrexate alone. Although it is probable that there is a small decrease in the efficacy of methotrexate, there are clear gains from the reduction in bone marrow toxicity and nausea.2 A weekly dose of 5 mg folate should routinely be given with methotrexate. Infliximab may be given to remove dependence on steroids, and there will inevitably be a period when the patient is receiving both agents. As in the case of azathioprine this should not be considered combination therapy, but rather a short-term, transitional, or weaning phase. However, there is literature favoring the combined use of conventional immunosuppressants alongside infliximab. The ACCENT 1 study showed better outcomes in those receiving infliximab who were already on, or who were concurrently started on azathioprine.3 This observation has been replicated,4 and should now be considered established practice for all those in whom azathioprine/6-mercaptopurine is tolerated. Comparable data in support of the methotrexate/infliximab combination exist,5 and patients unable to take a thiopurine should have background methotrexate alongside their infliximab. The combination of conventional immunosuppression with infliximab improves outcomes in terms of efficacy, (including a lower frequency of secondary loss of control), and leads to less overall toxicity. Fewer antibodies to infliximab occur. The most topical area is the so-called “top-down” approach. This strategy need not necessarily use multiple drugs, and in pediatrics the preemptive use of azathioprine has proved effective. However, the recent multicenter European study combined infliximab induction with the initiation of azathioprine, and yielded good results in the short term and out to 2 years.6 There was considerable avoidance of steroid exposure and little evidence of an increased risk of other toxicity. With only a single study the positive conclusions From the Department of Gastroenterology and Clinical Nutrition, University College Hospital, London, UK. Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20668 Published online in Wiley InterScience (www.interscience.wiley.com).