Background <p>The benefit of neoadjuvant radiation for esophageal squamous cell carcinoma (SCC) and adenocarcinoma (AC) remains controversial. This study comprised a histology-stratified pooled analysis of randomized controlled trials (RCTs) comparing neoadjuvant chemoradiation (nCRT) to neoadjuvant chemotherapy alone (nCT) for esophageal cancer.</p> Methods <p>A PRISMA 2020-compliant systematic review for RCTs comparing nCRT to nCT for esophageal cancer and a histology-stratified pooled random-effects meta-analyses were performed.</p> Results <p>Nine RCTs published from 2009 to 2024 were included, comprising 2174 patients (1083 nCRT, 1091 nCT). Of these, 1125 patients had AC (51.7%) and 1049 had SCC (48.3%). Most patients received cisplatin with 5-fluorouracil. Patients with SCC undergoing nCRT were more often resected (odds ratio [OR] 1.94; 95% confidence interval [CI] 1.05–3.60; <i>P</i>=0.03) and more often had a pathologic complete response (OR 8.78; 95% CI 3.27–23.57; <i>P</i>&lt;0.0001) than those undergoing nCT; R0 resection rates (OR 2.18; 95% CI 0.81–5.9; <i>P</i>=0.12) and anastomotic leaks (OR 0.91; 95% CI 0.55–1.49; <i>P</i>=0.70) were similar. For AC, nCRT was associated with similar resection rates (OR 0.90; 95% CI 0.49–1.64; <i>P</i>=0.72), similar pathologic complete response (OR 2.77; 95% CI 0.84–9.21; <i>P</i>=0.10), more R0 resections (OR 2.94; 95% CI 1.51–5.74; <i>P</i>=0.002), and similar leak rates (OR 1.10; 95% CI 0.71–1.70; <i>P</i>=0.67). nCRT was associated with fewer local recurrences for SCC (OR 0.58; 95% CI 0.40–0.86; <i>P</i>=0.006) but not AC (OR 1.04; 95% CI 0.70–1.53; <i>P</i>=0.86) (subgroup test <i>P</i>=0.04) and improved 3-year overall survival for SCC (OR 1.51; 95% CI 1.16–1.96; <i>P</i>=0.002) but not AC (OR 0.81; 95% CI 0.60–1.10; <i>P</i>=0.18) (subgroup test <i>P</i>=0.002).</p> Conclusions <p>Neoadjuvant radiation appears to confer meaningful improvement in long-term outcomes for SCC but not AC.</p>