Background: More than 50% unprecedented objective clinical response rate led to a rapid approval of anti-PD-1 antibodies by FDA using in patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL). However, anti-PD-1 monotherapy can induce complete remission (CR) only in about 10% patients. Decitabine, a demethylating agent, was documented to directly boost T cell function and also possibly delay/reverse PD-1-blocked T cell exhaustion. This Phase I/II study was designed to assess the safety and efficacy of decitabine-primed anti-PD-1 (SHR-1210, a novel humanized IgG4/kappa monoclonal antibody) treatment in r/r cHL patients. Methods: Enrolled patients without anti-PD-1 history were 1:2 assigned into SHR-1210 monotherapy (4 mg/kg per 3 weeks) cohort 1 or decitabine (10mg/d on day 1-5) plus SHR-1210 (4mg/kg, day 8, per 3 weeks) cohort 2. Patients refractory to anti-PD-1 monotherapy were allocated into cohort 2. Safety was assessed by CTCAEv4.0, and clinical response by PET-CT referred to standard international criteria. Results: A total of 57 patients with heavily treated history (14-cycle median systemic treatment or with average 8-cycle anti-PD-1 monotherapy) were enrolled and 41 completed serial response evaluation by the end of Jan. 2018. The most common adverse events were clinically negligible cherry hemangioma (75% in cohort 1 and 93% in cohort 2), and unattended leukocytopenia (32% in cohort 2). Six from 13 patients in cohort 1 were evaluated as 1 CR (17%), 2 PR (34%), and 3 SD. Twenty cases from cohort 2, before enrollment were evaluated to be refractory to anti-PD-1 alone therapy, 17 were evaluated and showed 4 CR (23%), 5 PR (30%), 4 SD, and 4 PD. Eighteen of 26 patients without anti-PD-1 history before enrollment were evaluated as 12 CR (67%), 4 PR (22%), and 2 SD. So far, 88% evaluated patients had a > 24-week progression-free survival. Conclusions: Addition of decitabine not only largely increased the CR rate of anti-PD-1 therapy in r/r cHL, but significantly reversed the resistance of anti-PD-1 therapy. Combination therapy had an acceptable safety profile. Clinical trial information: NCT02961101 and NCT03250962