It was reported that patients who contracted COVID-19 while taking clozapine exhibited a distinct hematological response. However, the absence of control groups made it difficult to attribute it to clozapine. The changes in absolute neutrophil counts (ANCs) during the 4 weeks after COVID-19 infection were compared between the two groups of patients with severe mental illnesses (SMIs) (49 patients using clozapine and 54 using other antipsychotics) using generalized additive modeling. Although the pattern of a transient drop in ANC followed by gradual recovery could be demonstrated in both groups, it was more pronounced in the clozapine group ( P = 0.00025). Nevertheless, overall ANC remained at a higher level in the clozapine group. The results suggested potential interaction between clozapine and COVID-19 at the level of hematological dynamics. However, it did not necessarily indicate that such interaction is inevitably harmful or dangerous. It was more of a concern that some patients using other antipsychotics exhibited decreased ANC, which did not easily recover. Traditionally, clinicians have been concerned about the worsening of hematological side effects in clozapine patients after COVID-19 infection. However, the obtained result highlighted the necessity of hematological monitoring in patients using any type of antipsychotics for SMIs.