Background: Resection of pulmonary metastasis (PM) is widely accepted to improve the prognosis in selected patients (pts) with metastatic colorectal cancer (CRC). However, the clinical implication of adjuvant chemotherapy after metastasectomy of PM is unknown. We conducted a multi-center phase 2 trial of adjuvant chemotherapy with mFOLFOX6 after metastasectomy of PM-CRC. Methods: Main eligibility criteria were first curative metastasectomy of 4 or less PMs and no prior chemotherapy except for adjuvant chemotherapy with fluoropyrimidine monotherapy after curative resection of primary or extrathoracic CRC metastasis. The study treatment was 12 courses of mFOLFOX6 (oxaliplatin 85 mg/m², l-leucovorin 200 mg/m², 5-fluorouracil 400 mg/m² bolus followed by 2400 mg/m² continuous infusion, every 2 w). The primary endpoint was overall survival (OS). The secondary endpoints included disease-free survival (DFS), adverse events (AEs), and recurrence sites. The sample size was determined to be 93 expecting 5-year OS rate of 50% with threshold 35% (90% power, alpha error 5%). Results: Fifty-two pts from 34 institutions were enrolled between July 2011 and July 2014. Patient enrollment was closed prematurely because of slow accrual. Four patients were ineligible after enrollment and the safety and efficacy cohort comprised 52 and 48 patients, respectively. Patient backgrounds were as follows: gender (male/female) 31/21, median age (range) 63 (42-75) years, ECOG PS (0/1) 48/4, primary site (colon/rectum) 18/34, number of PM (1/2/3/4) 36/9/5/2, synchronous/metachronous PM 11/41, and unilateral/bilateral PM 40/12. With the median follow-up time of 6.0 (1.8-7.7) years, 5-year OS rate was 86% (95% CI: 72-93) and 5-year DFS rate was 59% (95% CI: 43-71). Tumors recurred in 19 patients (13 lung, 3 liver and 7 others). Total 41 pts (79%) completed 12 courses of mFOLFOX6 (reasons for discontinuation: AEs in 3, refusal due to AEs in 8). AEs ( > Grade 3) were neutropenia 50%, fatigue 8%, peripheral sensory neuropathy 8%, appetite loss 4%, diarrhea 4%, febrile neutropenia 2% and allergic reaction 2%. There was no treatment related death. Conclusions: Adjuvant mFOLFOX6 is feasible and may be effective after metastasectomy for PM-CRC, considering much better OS than we had expected. Clinical trial information: UMIN000005693.