Here we report thrombocytosis in conventional cGKI null mutants (cGKIL1/L1) and gene-targeted cGKIα/β rescue mice (referred to as cGKI-SM) with cGKI expression specifically restored in smooth muscle (SM), but not in other cell types [2–4]. In contrast, conditional knockouts lacking the cGKI protein specifically in the megakaryocyte (MK)/platelet lineage (Pf4-Cretg/+; cGKIL2/L2) did not display a related thrombocytosis phenotype, indicating that the high platelet count of cGKIL1/L1 and cGKI-SM mutants is rather a reactive response than an intrinsic defect in megakaryopoiesis. In line with these findings, wild-type (WT) mice engrafted with cGKI-deficient bone-marrow (BM) cells showed full reconstitution of haematopoiesis and normal platelet counts upon myeloablative radiotherapy. Stimulation of BM-derived WT MKs using serum preparations from cGKI-SM mutants strongly accelerated megakaryopoiesis, suggesting that their high platelet counts develop in response to soluble factors. Indeed, we confirm elevated Interleukin-6 (IL-6) serum levels [5, 6], a known cause for reactive thrombocytosis, in cGKI-SM mutants, whereas IL-6 was unaltered in Pf4-Cretg/+; cGKIL2/L2 mice and cGKI-deficient BM chimaeras. Vice versa, antibody-mediated blockage of IL-6 reduced platelet counts in cGKI-SM mice, but not in WT mice.