OBJECTIVE The most advocated surgical technique to treat symptoms of isthmic spondylolisthesis is decompression with instrumented fusion. A less-invasive classical approach has also been reported, which consists of decompression only. In this study the authors compared the clinical outcomes of decompression only with those of decompression with instrumented fusion in patients with isthmic spondylolisthesis. METHODS Eighty-four patients with lumbar radiculopathy or neurogenic claudication secondary to low-grade isthmic spondylolisthesis were randomly assigned to decompression only (n = 43) or decompression with instrumented fusion (n = 41). Primary outcome parameters were scores on the Roland Disability Questionnaire (RDQ), separate visual analog scales (VASs) for back pain and leg pain, and patient report of perceived recovery at 12-week and 2-year follow-ups. The proportion of reoperations was scored as a secondary outcome measure. Repeated measures ANOVA according to the intention-to-treat principle was performed. RESULTS Decompression alone did not show superiority in terms of disability scores at 12-week follow-up (p = 0.32, 95% CI -4.02 to 1.34), nor in any other outcome measure. At 2-year follow-up, RDQ disability scores improved more in the fusion group (10.3, 95% CI 3.9–8.2, vs 6.0, 95% CI 8.2–12.4; p = 0.006, 95% CI -7.3 to -1.3). Likewise, back pain decreased more in the fusion group (difference: -18.3 mm, CI -32.1 to -4.4, p = 0.01) on a 100-mm VAS scale, and a higher proportion of patients perceived recovery as showing “good results” (44% vs 74%, p = 0.01). Cumulative probabilities for reoperation were 47% in the decompression and 13% in the fusion group (p < 0.001) at the 2-year follow-up. CONCLUSIONS In patients with isthmic spondylolisthesis, decompression with instrumented fusion resulted in comparable short-term results, significantly better long-term outcomes, and fewer reoperations than decompression alone. Decompression with instrumented fusion is a superior surgical technique that should in general be offered as a first treatment option for isthmic spondylolisthesis, but not for degenerative spondylolisthesis, which has a different etiology.