BACKGROUND Insulin resistance (IR) may play a role in most pathogenic processes that promote the development of late onset Alzheimer's disease (LOAD). This study was designed to evaluate whether galantamine influenced peripheral IR in LOAD. METHODS Ninety-five consecutive elderly patients, 40 LOAD and 55 non-demented patients were evaluated. IR was calculated with HOMA and modified-HOMA. All the patients were evaluated through comprehensive geriatric assessments at baseline and at 6, 12 and 18 months. RESULTS Over three 6-month periods of galantamine treatment, compared to the baseline values, there was a significant increase at 6 and 12 months in the MMSE and at 6 months in the IADL scores (t = 3.25, p = 0.002 and t = 2.69, p = 0.011 for MMSE; t = 2.03, p = 0.049; for IADL, respectively). Although, there was an improvement in MMSE and IADL scores of galantamine-treated patients, there was no significant change in IR indexes and correlation between IR indexes and cognitive status in both groups during the treatment period. CONCLUSIONS This study showed no relation between cognitive improvement and IR by galantamine therapy in AD. In conclusion, peripheral IR and central nervous system IR may be different, and galantamine itself may show its effects without affecting the insulin-signaling pathway.