Background: Many non-responders to azathioprine or mercaptopurine (6-mercaptopurine) have high normal thiopurine methyltransferase activity and preferentially metabolize mercaptopurine to produce 6-methyl-mercaptopurine instead of the active 6-tioguanine (6-tioguanine) metabolites. Aim: To describe the use of allopurinol in mercaptopurine/azathioprine non-responders to deliberately shunt metabolism of mercaptopurine towards 6-tioguanine. Methods: Fifteen thiopurine non-responders whose metabolites demonstrated preferential metabolism towards 6-methylmercaptopurine are described. Subjects were commenced on allopurinol 100 mg po daily and mercaptopurine/azathioprine was reduced to 25-50% of the original dose. Patients were followed clinically and with serial 6-tioguanine and 6-methylmercaptopurine metabolite measurements. Results: After initiating allopurinol, 6-tioguanine levels increased from a mean of 185.73 ± 17.7 to 385.4 ± 41.5 pmol/8 × 108 red blood cells (P < 0.001), while 6-methylmercaptopurine decreased from a mean of 10 380 ± 1245 to 1732 ± 502 pmol/8 × 108 RBCs (P < 0.001). Allopurinol led to a decrease in white blood cell from a mean of 8.28 ± 0.95 to 6.1 ± 0.82 × 108/L (P = 0.01). Conclusions: The addition of allopurinol to thiopurine non-responders with preferential shunting to 6-methylmercaptopurine metabolites appears to be an effective means to shift metabolism towards 6-tioguanine.