Pituitary tumors are characterized by increased expression of somatostatin receptor (SSTR) 2 and 5 subtypes that are acting as mediators of the somatostatin induced growth hormone inhibition. The aim of the study was to characterize the genetic variance of somatostatin receptor 5 (SSTR5) and investigate the possible correlation of identified polymorphisms with acromegaly and different disease characteristics as well as responsiveness to somatostatin analogs. In total 20 SNPs were identified in SSTR5 gene coding region and 2000bp upstream region by direct sequencing. 3 SNPs (C633T, T1004C and G1044A) were significantly associated with presence of acromegaly comparing 48 patients with acromegaly and 96 controls. These SNPs were further analyzed in the same group of acromegaly patients and 475 age and sex matched controls. The allele frequencies was significantly (p<0.001) different between the acromegaly patients and control group for two SNPs. Haplotype reconstruction revealed two possible risk haplotypes determined by 633T and 1044A alleles. Both haplotypes were found in significantly higher frequency in acromegaly patients compared to controls (P<0.001). In addition C633T was significantly associated with recurrent pituitary adenoma (higher number of adenoma resections) (P=0.0001), younger age at acromegaly diagnosis (P=0.002), increased BMI (P=0.004) and more aggressive adenoma proliferation in presence of somatostatin analogues therapy (P=0.014). We have thus identified the genetic variants of SSTR5 that may promote the pituitary adenoma development by low level suppression of tumor growth. These data suggest the important role of SSTR5 in the progression of acromegaly as well as possible identification of genetic markers that can be used to predict the recurrent pituitary tumors and potential choice of therapy.