This study investigates whether the reciprocal changes in transient receptor potential canonical (TRPC)1 and TRPC6 expressions, which have previously been observed in aging rat aorta, are functional in store-operated calcium (SOC) entry and proliferation in human vascular smooth muscle cells. TRPC1 levels were modulated via silencing and overexpression vectors in human primary aortic smooth muscle cells. Following TRPC1 gene modulation, TRPC1 and TRPC6 expression levels were measured using quantitative real-time RT-PCR. In functional analyses, real-time changes in intracellular calcium levels and cell proliferation were determined. Microarray analysis was performed to identify genes associated with functional alterations following TRPC1 silencing. TRPC1 expression was significantly increased in TRPC1-overexpressing cells and inhibited in TRPC1-silenced cells, as expected. TRPC6 expression was significantly decreased in TRPC1-overexpressing cells but not affected by TRPC1 silencing. SOC entry was significantly enhanced in TRPC1-silenced cells but not altered by TRPC1-overexpression. Furthermore, cell proliferation was correlated with changes in TRPC1 expression. Microarray analysis revealed that cell cycle-associated genes were significantly differentially expressed in TRPC1-silenced cells. In addition, STIM1 levels were downregulated significantly following TRPC1 silencing. Data suggest that TRPC1 has a functional role in SOC entry regulation as well as in human aortic smooth muscle cell proliferation.