Background: Neuroblastoma (NB) presenting with INRGSS MS metastatic pattern highlights the extreme heterogeneity within NB and subsequent difficulty in risk assignment. Depending on tumor biology, patients with stage MS disease may be classified as very-low risk or as high-risk. While outcomes at initial diagnosis have been well-described, outcomes after relapse are less well defined. Methods: From the INRG Data Commons, we investigated clinical and biological characteristics of patients diagnosed 1984-2021 with stage MS pattern NB (INSS stage 4s, INSS stage 4 or INRG stage MS) who subsequently experienced disease relapse or progression, excluding patients whose first event was death. Using Kaplan-Meier methods, post-relapse overall survival (OS)± standard error (SE) was calculated from the time of first relapse/progression until death or last contact, overall and by era of diagnosis: < 2000 vs ≥2001. Univariate Cox models were used to identify factors prognostic of post-relapse OS. Results: 209 patients met eligibility criteria,103 diagnosed < 2001 and 106 ≥2001. Of patients diagnosed ≥2001, 89% (n = 94) were < 365 days old at diagnosis; tumors were MYCN amplified in 21% (21/102) and diploid in 31% (20/64). Of this same cohort, time from initial diagnosis to relapse was < 6 months in 40% (n = 42), 6-12 months in 25% (n = 26), and > 12 months in 36% (n = 38) of patients. Of 60 patients with known site of relapse/progression diagnosed ≥2001, 73% (44) were metastatic (29) or primary plus metastatic (15). Among these, 16% (5/32) remained stage MS pattern while 84% (27/32) had metastatic sites beyond MS sites. Five-year post-relapse OS±SE was 53±3.5% overall (n = 209), and higher for those diagnosed ≥2001 (62±5.0%; n = 106) compared to those diagnosed < 2001 (44±4.9%; n = 103) (p = 0.0046). In patients diagnosed ≥2001, factors prognostic of superior post-relapse OS included: age < 365 days; not Hispanic; MYCN non-amplified; no 1p loss/aberration, hyperdiploidy; low/intermediate MKI; LDH < 1400 U/L, favorable INPC histology; and < 12 months from initial diagnosis to first relapse. Conclusions: Most patients with relapsed stage MS NB have metastatic relapse and these relapses more commonly occur at sites outside liver, skin, and bone marrow. Patients diagnosed ≥2001 with MS pattern NB have substantially better post-relapse OS compared to those diagnosed < 2001. In the cohort of patients with MS pattern NB diagnosed ≥2001, most of the well-accepted prognostic factors for OS at diagnosis are also prognostic of post-relapse OS.