OBJECTIVE To estimate the impact of toxicity related to nucleoside analogue reverse transcriptase inhibitors (NRTI) on the total cost of medical care in HIV-1-infected patients. METHODS . A pharmacoeconomic model was developed from the data obtained by a prospective, observational, multicenter study performed in Spain (Recover). The study patients had developed one NRTI-associated adverse event (AE) that justified discontinuation of treatment with the drug. All costs derived from NRTI-associated AEs in the HAART regimens of HIV-1-infected patients over a period of one year were assessed. The cost assessment (2005 values) included direct medical costs (drugs and AE management) and indirect costs (loss of productivity). The healthcare resources used in AE management were estimated by an expert panel of clinicians. RESULTS The use and cost of resources rose with increasing severity of all the AE. The average total cost per patient was estimated to be 4012 euro, which included 1789 euro in drug costs (NRTI associated with therapy discontinuation due to AE), and 2223 euro in direct and indirect costs of AE management (45% and 55% of total cost, respectively). Seventy-three per cent of AE-associated costs per patient came from lipoatrophy (560 euro), lipodystropy (535 euro) and peripheral neuropathy (533 euro). CONCLUSIONS Management of NRTI-related toxicities is more costly than NRTI acquisition and produces a significant increase in the overall healthcare expenditure for HIV-1-infected patients. This fact should be taken into account when designing the most efficient antiretroviral treatment strategies.