BACKGROUND In the rat liver, growth hormone (GH) affects the synthesis of vitamin-K-dependent factors, including Protein C (prot.C) and protein S (prot.S), two natural anticoagulants that prevent hypercoagulable states. Adults with GH deficiency (GHD) are at risk of thrombotic events. High circulating levels of PAI-1 and t-PA, that reflect hypercoagulable states, may contribute to such risk. In GHD adults on replacement therapy with recombinant human GH (r-HGH), %Δ PAI-1 and %Δ t-PA are related to %Δ insulin changes. OBJECTIVES To evaluate changes in vitamin-K-dependent factors in GHD on r-HGH replacement. METHODS In 60 GHD adults, to relate plasma levels of vitamin-K-dependent factors with those of PAI-1, t-PA and insulin before and after 6-month (6-mo) replacement therapy with r-HGH. RESULTS After 6-mo r-HGH replacement, %Δ insulin enhancements occurred in 36/60 subjects. PAI-1, t-PA, Prot.C, Prot.S and FVIIact did not change in them. In the 24/40 subjects that experienced %Δ insulin reductions, Prot.C (p=0.025), Prot.S (p=0.031) and FVIIact (p=0.049) decreased significantly. PAI-1 (p=0.019) and t-PA antigen (p=0.009) behaved similarly. In a multivariate analysis, %∆ PAI-1 (β=0.436, p<0.01) was the strongest predictor of %∆ prot.S, wheras %∆ t-PA (β=0.385, p<0.008) and %∆ insulin (β=0.429, p<0.004) were the strongest predictors of %∆ prot.C. In all cases, regardless of %Δ insulin changes, FII, FVII Ag and FIX levels did not change from baseline. CONCLUSIONS In GHD adults on r-HGH replacement, changes in vitamin-K-dependent factors reflect a subtle adaptation of the natural anticoagulant system to PAI-1 and t-PA changes, via the response of insulin to r-HGH.