Objective To investigate the clinical significance of changes in platelet parameters in patients with secondary failure of platelet recovery (SFPR) and cytomegalovirus (CMV) infection after hematopoietic stem cell transplantation (HSCT). Methods In this retrospective study, 79 patients who had undergone allogeneic HSCT (allo-HSCT), including 40 patients with SFPR and 39 patients without SFPR, were recruited. The evaluated parameters were platelet count (PLT), plateletcrit (PCT), platelet-large cell ratio (P-LCR), mean platelet volume (MPV), platelet distribution width (PDW), the incidence of CMV infection after allo-HSCT, and the correlation of SFPR and CMV infection in patients who had undergone allo-HSCT. The control group included 107 healthy donors. Results The SFPR group had significantly lower megakaryocyte counts, PLT, and PCT and significantly higher P-LCR, MPV, and PDW than the healthy donor and non-SFPR groups. The incidence of CMV infection was higher in SFPR patients than in non-SFPR patients. Among the patients with SFPR, P-LCR, MPV, and PDW were lower in those with CMV DNA >8000 copies/mL than in those with CMV DNA <8000 copies/mL ( P < .05 for all); the CMV viral load was slightly negatively correlated with MPV ( P = .0297) and P-LCR ( P = .0280). Conclusion We demonstrate for the first time that the level of platelet activation in SFPR patients, which was closely related to CMV infection, was higher than that in that in non-SFPR patients, and higher CMV load was associated with the inhibition of platelet activation.