Aim: To conduct a pragmatic, randomized controlled trial to assess whether thiopurine methyltransferase (TPMT) genotyping prior to azathioprine reduces adverse drug reactions (ADRs). Methods: A total of 333 participants were randomized 1:1 to undergo TPMT genotyping prior to azathioprine or to commence treatment without genotyping. Results: There was no difference in the primary outcome of stopping azathioprine due to an adverse reaction (ADR, p = 0.59) between the two study arms. ADRs were more common in older patients (p = 0.01). There was no increase in stopping azathioprine due to ADRs in TPMT heterozygotes compared with wild-type individuals. The single individual with TPMT variant homozygosity experienced severe neutropenia. Conclusion: Our work supports the strong evidence that individuals with TPMT variant homozygosity are at high risk of severe neutropenia, whereas TPMT heterozygotes are not at increased risk of ADRs at standard doses of azathioprine ; William G. Newman*, Katherine Payne*, Karen Tricker, Stephen A Roberts, Emily Fargher, Sudeep Pushpakom, Jane Alder, Gary Sidgwick, Debbie Payne, Kay Poulton, Rachel Elliott, Robert Elles, Simon Ramsden, Julie Andrews, Brian Houston, Faeiza Qasim, Jon Shaffer, Christopher Griffiths, David W Ray, Ian Bruce, TARGET study physicians, William ER OllierLancet - rejected without review30/7/09 - sub to BMJ - sent out for review!20/12/09 - rejected21/1/10: resub to Clin Pharm Ther3/1/10 - rejected but appealing-REJECTED!AIM submitted 7th July 2010major changesResubmitted 17/9/10REJECTEDSub CMAJ 5/10/10rejected 6/12/10Resub to Pharmacogenomics Jan 2011accepted 22/2/11 - due in print June 2011Posted online on 3 May 2011.(No subscription!)Impact Factor: 3.876 (2010)