Dietary zinc is an important trace element in the body and is related to both cell proliferation and growth arrest. A recent study found that the extracellular zinc sensing receptor trigger intracellular signal transduction in HT29 human colorectal cancer cells. However, the signaling mechanism causing this growth regulation by extracellular zinc is not clearly understood. When we treated non-toxic 10 and 100 µM levels of ZnCl₂, HT29 cell growth and proliferation increased and decreased, respectively, in a minimally serum starved medium (MSSM). A lack of a significant increase in intracellular zinc levels by zinc treatment suggested that this differential growth regulation of HT29 cells by extracellular zinc is acquired by receptor mediated signal transduction. Moreover, this zinc induced growth regulations was differentially affected by PD98059, suggesting the involvement of the ERK pathway. Transient ERK activation and subsequent cyclin D1 induction were observed upon treating 10 µM of ZnCl₂ in MSSM, in the presence of cell proliferation. On the other hand, prolonged ERK activity was observed with a subsequent increase of cyclin D1 and p21^Cip/WAF1 upon treating with 100 µM of ZnCl₂ in MSSM, and this was associated with non-proliferation. Moreover, this ERK activation and cyclin D1 and p21^Cip/WAF1 induction were abolished by PD98059 pre-treatment. The differential regulations of cell growth, ERK activities, and cyclin D1 and p21^Cip/WAF1 inductions were also observed in serum enriched medium containing higher zinc concentrations. Therefore, differential cell cycle regulator induction occurs by a common ERK pathway in the differential growth regulation of HT29 cells by extracellular zinc.