BACKGROUND: The adequacy of exposure of purine analogs as measured by 6-thioguanine nucleotides concentrations in the setting of combination therapy remains poorly understood. The aim of this study was to investigate the relationship between the mean corpuscular volume (MCV) value (as a surrogate marker of 6-thioguanine nucleotides concentration) and Crohn's disease outcomes in the setting of combination therapy with infliximab. METHODS: The SONIC trial was a randomized controlled trial comparing infliximab to azathioprine and to infliximab plus azathioprine in 508 Crohn's disease patients. An increase of at least 7 femtoliter (fL) of the MCV (DeltaMCV) was used for statistical analysis. RESULTS: At week 26, the mean increase of MCV was similar among patients treated with azathioprine alone (mean of 7.9 fL) or in combination with infliximab (mean of 8.5 fL). In the azathioprine group, 63.6% of patients with DeltaMCV >7 were in steroid-free clinical remission at week 26 as compared with 33.3% of patients without DeltaMCV >7 (P = 0.0046). In the combination therapy group, DeltaMCV above 7 was associated with mucosal healing (75.0% for DeltaMCV >7 versus 47.1% for DeltaMCV <7, P = 0.0172) but not with steroid-free clinical remission. Patients with a DeltaMCV above 7 were more likely to have infliximab trough level above 3 mug/mL at week 30 (68.4% versus 38.8% for DeltaMCV <7, P = 0.0032). CONCLUSIONS: These results suggest that DeltaMCV above 7 (which is a surrogate for a higher 6-thioguanine nucleotides concentration) leads to improved Crohn's disease outcomes, even when combined with infliximab. It also suggests the possibility that a lower azathioprine exposure might be less effective in combination therapy.