Beta thalassemia is known to be characterized by a hypercoagulable state, with prothrombotic factors present and thrombotic event development in a number of patients. The aim of the present study was to evaluate subclinical involvement of the central nervous system (CNS) in young patients with thalassemia intermedia, the use of nonimaging, noninvasive laboratory methods for detecting relevant abnormalities, and the frequency and possible correlation of coagulation abnormalities with CNS lesions. In this cross-sectional study, 24 young patients with thalassemia intermedia were evaluated (mean age 12 ± 4.6 years, range 4.5-20 years). Patients underwent neurological examination, inherited and acquired coagulation defect testing, as well as neurophysiologic and neuroimaging evaluation. Patients aged 6-16 also had intelligence scores measured. With regards to coagulation, a decrease in antithrombin III (ATIII), protein C and protein S activity was found in 4.1, 54.16 and 45.8% of patients, respectively. Increased D-dimers, as well as thrombin-antithrombin complex (TAT) and prothrombin fragment (F1 + 2) values were found in 12.5, 62.5 and 8.33% of patients, respectively. Heterozygosity and homozygosity for the methylenetetrahydrofolate reductase mutation was found in 45.8 and 12.5% of patients, whereas heterozygosity for factor V Leiden and G20210FII was found in 8.33 and 12.5% of patients, respectively, with increased prevalence compared to Greek population. Neuroimaging evaluation was normal in all patients. Neurophysiologic evaluation revealed abnormal findings in 33.3% of patients on electroencephalogram (EEG), 16% on brain auditory-evoked potentials (BAEPs) and 4.12% on somatosensory evoked potentials (SEPs). Visual-evoked potentials (VEPs) were normal in all patients. A statistically significant difference was found between low protein C values, as well as high platelet counts, with abnormal EEG findings (P = 0.004 and P = 0.039, respectively). Transcranial Doppler (TCD) measurements revealed increased peak systolic velocities in anterior and posterior cerebral arteries and in basilar artery in 57, 38 and 41% of patients, respectively, as compared to healthy population values. On the contrary, decreased mean velocities were found both on middle cerebral artery and pars terminalis of internal carotid examination in 28.5% of patients. Patients with pathological findings on TCD study had lower hematocrit (P = 0.049) and younger age (P = 0.001) than patients with normal measurements. With regards to intelligence scores, mean intelligence quotient (IQ) was 100 ± 19.1, with 11.7% of patients demonstrating IQ below 85. The study results confirm the early presence of hemostatic changes in patients with thalassemia intermedia. Additionally, they demonstrate subclinical CNS involvement starting at childhood. For such involvement detection, in addition to neuroimaging, neurophysiological and neuropsychological evaluation is warranted.