Single-photon emission-computed tomography (SPECT) may potentially contribute to the diagnostic work up of patients with neurodegenerative dementia. This systematic review aims to establish the diagnostic utility of 99mTc-hexamethylpropyleneamine (99mTc-HMPAO) and 99mTc-ethylcysteine dimer SPECT in distinguishing between Alzheimer's disease (AD) and frontotemporal dementia (FTD), AD and vascular dementia (VD), AD and dementia with Lewy bodies (DLB), and AD and normal controls (NC). We searched MEDLINE and Embase databases via OVID for articles from January 1985 to May 2012 and identified additional studies from reviews and references. Of 755 studies, 49 studies met the inclusion and exclusion criteria for this systematic review; AD versus FTD (n=13), AD versus VD (n=18), AD versus DLB (n=5), and AD versus NC (n=18). We compiled relevant data and graded the studies with an internal and external validity criteria checklist. We pooled the studies with a clinical diagnosis and those using 99mTc-HMPAO SPECT in a meta-analysis, calculating the pooled weighted sensitivity, specificity, likelihood ratios, and diagnostic odds ratios using DerSimonian-Laird random-effects model. The pooled weighted sensitivity and specificity of 99mTc-HMPAO-SPECT in distinguishing clinically diagnosed AD from FTD are 79.7 and 79.9%, respectively, AD from VD are 74.5 and 72.4%, AD from DLB are 70.2 and 76.2%, and AD from NC are 76.1 and 85.4%. SPECT does have diagnostic value, particularly in differentiating Alzheimer's disease from frontotemporal dementia and normal controls; however, it should not be used in isolation, rather as an adjunct, and interpreted in the context of clinical information and paraclinical test results.