Abstract Background The incidence of thyroid cancer is increasing worldwide. A third of new thyroid cancer cases are small papillary thyroid cancer (1.5 cm or less in size). Although surgical intervention is the most common management option for patients with small papillary thyroid cancer (SPTC), active surveillance (AS), radiofrequency ablation (RFA), laser ablation (LA), and microwave ablation (MWA) are also considered as management alternatives. This study aimed to assess the comparative effectiveness of surgical (TS) vs. non-surgical management options for patients with SPTC. Methods We included studies comparing any type of TS versus AS, LA, RFA, or MWA in patients with a biopsy-proven SPTC of less than 1.5 cm without evidence of preoperative local or distant metastasis. The outcomes of interest were risk of recurrence of thyroid cancer, disease-specific mortality, and quality of life (QoL). All outcomes were measured at the longest follow-up. Literature search used Cochrane Database, Embase, and MEDLINE from inception to June 3rd, 2020. The CLARITY tool was used to assess the risk of bias. For dichotomous outcomes, we calculated odds ratios (OR) and their corresponding 95% confidence intervals (CI) using random-effects models. We estimated mean differences (MD) and standardized mean differences (SMD) based on predetermined criteria for continuous outcomes. PROSPERO (CRD42021235657). Results We included 14 retrospective cohort studies consisting of 6457 patients. TS, AS, RFA, MWA, and LA therapies were performed in 67.50% (n=4291), 21.03% (n=1337), 7.53% (n=479), 2.49% (n=255), and 1.27% (n=81) of cases, respectively. Disease-specific mortality (mean follow-up ranged from 37.5 to 120.0 months) was not different between patients who underwent TS versus AS. There was no data on mortality for the other noninvasive approaches. The risk of recurrence (mean follow-up ranged from 17.0 to 49.2 months) was not different when comparing LA, RFA, AS, or MWA against TS. The overall physical health domain of QoL (mean follow-up ranged from 10.8 to 29.6 months) was increased in patients who underwent AS (SMD: 0.23 95%CI 0.09; 0.37, k=2, I2=0.00%) compared to TS, but it was no different when comparing MWA or RFA versus TS. In addition, there were no differences in the overall mental health domain of QoL comparing AS or RFA vs TS. The risk of bias was considered moderate in nine studies and high in five studies. Conclusion Low evidence quality suggests equal risk of recurrence and mortality between SPTC patients who underwent minimally invasive treatment modalities or active surveillance compared to surgery. However, physical QoL was better in SPTC patients who underwent AS. Further studies are needed to confirm these results and draw robust conclusions. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.