The currently accepted treatment paradigm of treating chronic rhinosinusitis (CRS) first with appropriate medical therapy (AMT) and then with surgery if patients are refractory to AMT, has been criticized for lack of evidence. The objective of this study was to reassess the literature and establish the highest level of evidence possible regarding further management of CRS patients refractory to AMT. This study was a systematic review (SR) with meta-analysis (MA). Adult CRS patients who received AMT and then underwent either medical or surgical therapy in moderate to high level prospective studies were included. Outcomes assessed were disease-specific quality of life (QOL), nasal endoscopy, health-state utility, missed work days, change in cardinal symptoms of CRS, economic impact, and adverse events. A total of 970 manuscripts were identified; 6 studies were ultimately included in the SR with 5 included in the MA. Compared to continued medical therapy, endoscopic sinus surgery (ESS) significantly improved patient-based QOL scores (p < 0.00001) and nasal endoscopy scores (p < 0.00001). Difference in missed work days depended heavily on patient choice of intervention. Unpooled analysis showed improvements in olfaction, health utility scores, and cost-effectiveness. On meta-analysis, for CRS patients refractory to AMT, ESS significantly improves objective endoscopic scoring outcomes vs continued medical therapy alone. In patients with refractory CRS who have significant reductions in baseline QOL, ESS results in significant improvements. Continued medical therapy appears to maintain outcomes in patients with less severe baseline QOL. Unpooled analysis demonstrates improvement in health utility, olfaction, and cost-effectiveness following ESS compared to continued medical therapy alone, in medically refractory CRS.