Purpose <p>Ankylosing spondylitis (AS) is a progressive, chronic inflammatory rheumatic disease. Long non-coding RNAs (lncRNAs) are vital regulators for AS. This study aims to explore peripheral blood lncRNA LOC645166 expression in AS patients and its correlation with disease activity.</p> Methods <p>Totally, 78 AS patients and 71 healthy volunteers were selected as the research subjects, with their demographics compared. The disease activity and spinal functional impairment of AS patients were assessed using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scales. Peripheral blood lncRNA LOC645166 expression before or after&#xa0;treatment in AS patients and its correlations with BASDAI and BASFI scores were assessed by RT-qPCR and Spearman’s correlation analysis, respectively. Receiver operating characteristic curves were used to analyze the diagnostic efficacy of C-reactive protein (CRP) and&#xa0;peripheral blood lncRNA LOC645166 in&#xa0;aiding in the diagnosis of AS and the value in evaluating AS patients with active disease.</p> Results <p>The proportion of patients with AS family history, WBC, and NEUT was increased in the AS patients versus the healthy controls. Peripheral blood lncRNA LOC645166 was poorly expressed in AS patients and was significantly negatively correlated with BASDAI and BASFI beore or after&#xa0;treatment. Peripheral blood lncRNA LOC645166 &lt; 0.78 (area under the curve [AUC] = 0.712) could assist in AS diagnosis. Peripheral blood lncRNA LOC645166 &lt; 0.25 (AUC = 0.754) showed a diagnostic potential for active AS.</p> Conclusion <p>Lowly&#xa0;expressed peripheral blood lncRNA LOC645166 in AS patients has a .high diagnostic value for both AS and active AS, which can provide effective guidance for AS clinical diagnosis.</p>