Background: The effect of complete macroscopic excision (CME) of the primary tumour on event free survival (EFS) in high-risk neuroblastoma remains controversial. We therefore investigated the influence of CME in patients enrolled on the HR-NBL1/SIOPEN Trial and compared the effect in the pre immunotherapy era. Methods: Eligibility criteria were: inclusion in HR-NBL1/SIOPEN Trial between 2002-2015, stage 4 disease; completion of Rapid COJEC induction ± 2 courses of TVD; no progression/relapse/death; no prior attempt at resection and complete operation data. Intended therapy following operation comprised: HDT/SCT (BuMel or CEM, after 2011 BuMel), 21Gy radiotherapy to the primary site, 13-cis RA and after 2009 ch14.18/CHO antibody ± IL2 in addition. 1504 patients fulfilled these criteria; 737 were treated prior to ch14.18/CHO availability (2002-2009) and 767 in the immunotherapy era. Median observation time was 4.9 years (0.1-14 years). Results: CME was achieved in 77%, incomplete macroscopic excision (IME) in 21% and 2% were inoperable (0E). Surgical mortality was 0.46% (7/1504). Five year event-free survival (5y-EFS ± standard error) was 39%±2% with CME and 30%±3% with IME or 0E (p = 0.002). The cumulative incidence of local relapse (CILR) was 0.17±0.01 (CME); 0.31±0.03 (IME) and 0.42 ±0.10 (0E) (p < 0.001). 88% of patients received radiotherapy (78% CME; 21% IME and 1% 0E). 5y-EFS for patients with CME who received radiotherapy was 44±2%, but 31±6% without (reasons included very young age and very large primary tumours) (p = 0.013) and 35±3% with less than CME compared to 20±1% without radiotherapy (NS). CILR was 0.14±0.01 in patients with CME who received radiotherapy compared to 0.28±0.06 in patients who did not (p = 0.005). 5y-EFS was significantly higher (42±2%) for patients enrolled after 2009 compared to before (32±2%) (p = 0.000). 5-y EFS for patients after 2009 who achieved CME was 45±2% vs. 36±2% after IME and 26±13% after 0E respectively (p = 0.034); compared to 33±2% vs. 26±4% (IME) and 17±11% (0E) (p = 0.059) prior to 2009. Conclusions: In the immunotherapy era, CME in Stage 4 patients who received local radiotherapy resulted in improved 5-EFS. Clinical trial information: NCT01704716