Aim To investigate the effects of calcium blocker nifedipine and diuretic hydrochlorothiazide on mechanical stretch stress mediated phosphorylation of ERK1/2 （p-ERK1/2） and expression of Ki67 in vascular smooth muscle cells （VSMC）. Methods Cultured quiescent VSMC were pretreated with nifedipine and hydrochlorothiazide respectively and subjected to treatment with mechanical stretch stress. Level of p-ERK1/2 in the treated cells was detected by Western blot and meanwhile Ki67 expression was detected by immunofluorescent staining. Results Compared with the negative control group, nifedipine or hydrochlorothiazide had no effects on p-ERK1/2 and Ki67 expression in quiescent VSMC, while mechanical stretch stress stimulation significantly increased levels of p-ERK1/2 and Ki67 expression, which was inhibited by nifedipine in a concentration-dependent manner, and synergistically enhanced by hydrochlorothiazide. Conclusions Hydrochlorothiazide synergistically promotes increased p-ERK1/2 and Ki67 expression in VSMC induced by mechanical stretch stress, which can be inhibited by nifedipine in a concentration-dependent manner. These results provide novel mechanisms for traditional antihypertensive drugs.