Unlike lymphodepletion, a decrease in platelet count following induction immunosuppressive therapy with polyclonal rabbit antithymocyte globulin (rATG) is deemed as an adverse event. However, this phenomenon may represent a particular rATG antirejection mechanism. This retrospective single-center study included 156 patients who received a heart transplant (HTx) between 2010 and 2018. All patients received rATG induction therapy for 5 days. Absolute lymphocyte count (ALC) and platelet counts were assessed on days 0, 7, and 14 following HTx. The primary outcome of the study was the first occurrence of acute cellular rejection (ACR) defined as grade ≥ 1B within 24 months after HTx. Both ALC and platelet counts decreased rapidly after induction. During the 24-month follow-up period, 17% of patients had ACR. Patients with ACR had significantly higher platelet count on day 7 (145 vs 104, P < .001) and higher ALC on day 14 (162 vs 130, P = .035) than those without rejection. Patients in the highest platelet count quartile showed more ACR (50% in quartile 4 vs 0% in quartile 1, P = .006) as well as a higher cumulative total rejection score. Univariate analysis showed that ACR was associated with platelet count on day 7, recipient age, and pretransplant cytomegalovirus IgG serology. In multivariable regression analysis, platelet count on day 7 was the most accurate predictor of ACR. Lower platelet count after induction with rATG is associated with less ACR. This suggests platelet involvement in antirejection mechanisms of rATG and a possible rationale for targeting platelets in future immunosuppressive strategies. •Platelet count after rabbit antithymocyte globulin induction is associated with heart transplant rejection.•Lower platelet count on day 7 but not day 14 is related to less allograft rejection.•This indicates platelet involvement in alloimmunity early after transplant.