Objectives We investigated the role of long non-coding (lnc) RNA-NEF (neighboring enhancer of FoxA2), a characterized oncogene in cancer biology, in postmenopausal osteoporosis and its diagnostic and prognostic value in this disease. Methods Expression of lncRNA-NEF in plasma was detected by RNA extraction and real-time quantitative PCR. The diagnostic value of lncRNA-NEF and interleukin (IL)-6 for postmenopausal osteoporosis was evaluated by receiver operating characteristic curve analysis, with postmenopausal osteoporosis patients as true positive cases and healthy volunteers as true negative cases. Results We showed that plasma lncRNA-NEF was downregulated and plasma IL-6 was upregulated in postmenopausal osteoporosis patients compared with healthy controls. Altered plasma levels of lncRNA-NEF and IL-6 separated postmenopausal osteoporosis patients from healthy controls, and lncRNA-NEF and IL-6 were inversely and significantly correlated in osteoporosis patients. Patients were divided into high (n = 68) and low lncRNA-NEF (n = 73) groups according to Youden's index. Patients with high lncRNA-NEF levels required a significantly shorter treatment course and had a lower post-treatment recurrence rate. Conclusion We showed that lncRNA-NEF is downregulated in postmenopausal osteoporosis and is related to course of treatment and recurrence. The involvement of lncRNA-NEF in postmenopausal osteoporosis is likely related to IL-6.