The combination of tenofovir and didanosine results in an increase in the didanosine plasma exposure and might augment the risk for didanosine toxicity. Although pharmacokinetic studies support a didanosine dose reduction to 250 mg when used concurrently with tenofovir in patients weighing at least 60 kg, no data are available in lower-weight patients. We describe a case of lactic acidosis and acute liver failure in a low-weight patient receiving tenofovir and a reduced dose of didanosine (200 mg/day). To our knowledge, this is the first case of severe toxicity associated with a reduced dose schedule of didanosine. Previous cases of severe toxicity associated with the combination of tenofovir and didanosine are reviewed.