Ibrutinib, obinutuzumab plus venetoclax demonstrate synergy in pre-clinical models of mantle-cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multi-center prospective phase I/II trial, aimed to determine the maximum tolerated dose (MTD) of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide-quantitative polymerase chain reaction (ASO-qPCR). Between Oct 14, 2015 to May 29, 2018, forty-eight patients were enrolled. No dose limiting toxicity (DLT) was reported, and venetoclax at 400mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events (AEs). The complete response rate assessed by positron-emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10 out of 14) and 100% of untreated MRD-evaluable patients (n=12), at the end of three cycles. The median follow-up (mFU) for relapsed patients was 17 months (range, 10 to 35). The 2-years PFS was 69.5% (95% CI, 52.9- 91.4%) and 68.6% (95% CI, 49.5- 95.1%) for OS. The mFU was 14 months (range, 5 to 19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5- 100%). Obinutuzimab, ibrutinib and venetoclax combination is well tolerated and provides high response rates including at the molecular level in relapsed and untreated MCL patients.