The association of sFRP4 expression with aggressiveness and recurrence of growth hormone (GH)-secreting pituitary adenomas was investigated. Ten normal pituitary and 52 GH-secreting pituitary adenoma specimens were classified into three groups: normal pituitary (control) group, non-aggressive group, and aggressive group, according to preoperative evaluation by magnetic resonance imaging (MRI)/computed tomography (CT). Expression of sFRP4 was determined by quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis, and tissue microarrays, to assess the association between sFRP4 and aggressiveness. Follow-up information of all 52 patients was collected to evaluate the impact of sFRP4 expression on the recurrence/progression of GH-secreting pituitary adenomas. qRT-PCR results showed a lower level of sFRP4 mRNA in the aggressive group, as compared to that in the non-aggressive group (P=0.001). A similar trend was observed on western blot analysis for sFRP4 protein expression (P=0.004). On analysis by tissue microarrays, weak sFRP4 expression was detected in the aggressive group (10/15, 66.7%). Univariate analysis showed a significant relationship between low sFRP4 expression and aggressiveness (P=0.024). On multivariate analysis weak sFRP4 expression was found to be an independent factor of recurrence/progression (odds ratio: 0.063, P=0.026). Methylation of the sFRP4 promoter was increased in low sFRP4 staining group compared to that in the high sFRP4 staining group (P<0.001). In this study, weak sFRP4 expression appeared to predict aggressive behavior, and was associated with recurrence/progression of GH-secreting pituitary adenomas. Methylation of the sFRP4 promoter may account for the low sFRP4 expression.