Oral zinc (Zn(2+)) is often employed for treating hair loss, even in the absence of zinc deficiency, although its mechanisms of action and efficacy are still obscure. In the current study, we explored the in vivo effects of oral zinc using the C57BL/6 mouse model for hair research. Specifically, we investigated whether continuous administration of high-dose ZnSO(4) x 7H(2)O (20 mg/ml) in drinking water affects hair follicle (HF) cycling, whether it retards or inhibits chemotherapy-induced alopecia (CIA) and whether it modulates the subsequent hair re-growth pattern. Here, we show that high doses of oral zinc significantly inhibit hair growth by retardation of anagen development. However, oral zinc also significantly retards and prolongs spontaneous, apoptosis-driven HF regression (catagen). Oral zinc can also retard, but not prevent, the onset of CIA in mice. Interestingly, Zn(2+) treatment of cyclophosphamide-damaged HFs also significantly accelerates the re-growth of normally pigmented hair shafts, which reflects a promotion of HF recovery. However, if given for a more extended time period, zinc actually retards hair re-growth. Thus, high-dose oral zinc is a powerful, yet ambivalent hair growth modulator in mice, whose ultimate effects on the HF greatly depend on the timing and duration of zinc administration. The current study also encourages one to explore whether oral zinc can mitigate chemotherapy-induced hair loss in humans and/or can stimulate hair re-growth.