At present there is no widely accepted therapy for ankylosing spondylitis (AS), a progressive debilitating disease. The effectiveness of sulfasalazine in AS still lacks strong evidence, as well, the magnitude of its benefit is unknown. A meta-analysis was carried out to assess the effectiveness of sulfasalazine in AS. A search of the literature was done using Medline, Index Medicus, the reference lists of articles located and contacting content experts to reveal unpublished studies. Five randomized controlled trials (RCT) comparing sulfasalazine to placebo were located and assessed methodologically. The methodologic quality of all 5 RCT was considered satisfactory and consequently these studies were included in the meta-analysis. The pooled estimate of clinical benefit (and its 95% confidence interval) favoring sulfasalazine, over and above that observed in the placebo group was as follows: Duration of morning stiffness -28.2% (-54.6 to -1.8%); severity of morning stiffness -30.6% (-52.5 to -8.7%); severity of pain -26.7% (-44.3 to -9.1%); general well being -7.1% (-24.3 to 10.0%); erythrocyte sedimentation rate -9.2% (-24.8 to 6.4%); and IgA -11.7% (-18.8 to -4.7%). Adverse effects, mostly mild, were more frequently observed in the sulfasalazine group (odds ratio [OR] = 1.5746, p = 0.1082). The occurrence of dropouts (OR = 1.1554, p = 0.6119) was similar in both groups. Sulfasalazine is a safe and effective drug in the short term treatment of AS.