Objectives. To test in a large open study whether thalidomide is potentially useful in treating ankylosing spondylitis, and to see if thalidomide induces any change in expression of genes in peripheral blood mononuclear cells (PBMC). Methods. Thirty male patients with treatment-refractory ankylosing spondylitis were recruited into a 12-month open study using thalidomide at a dosage of 200mg/day. Seven indices were measured as primary outcome measures, and 6 other indices as secondary outcome measures. Transcripts in the PBMC of some of these patients were first screened with microarray, and then measured with reverse transcriptase-polymerase chain reaction. Results. Twenty-six patients completed the study. Of these, 80% showed a >20% improvement in 4 of 7 primary indices. Sharp declines in several parameters were noticed at 3-6 months. Nine patients became pain-free. There was also a statistically significant decrease in tumor necrosis factor α transcripts in the PBMC. Conclusion. Thalidomide is a reasonably promising drug in treatment-resistant ankylosing spondylitis.