The apoptotic effect is an important issue in cancer treatment. To achieve this goal, an atmospheric plasma jet (APJ) was set up for use on cultured cells in a temperature-controlled environment. Melanoma skin cancer and normal skin cells were targeted with this device. Following a 5 s plasma exposure, there was a 67% cell death in melanoma skin cancer cells compared with 5% in normal skin cells as measured after 24 h. When the treatment time was increased to 15, a 98% cell death was reported for melanoma skin cancer cells, which was 80% greater than the cell death in normal skin cells. Our observations further indicate that this preferential cell death is largely due to apoptosis. It shows that an APJ is a selective device in the induction of apoptosis in cancer and normal cells. APJ was shown to affect cells directly and indirectly through a plasma-activated medium (PAM). In direct treatment, cells were exposed to plasma while suspended in a culture medium, and in indirect treatment, cells were added to a culture medium previously activated by plasma treatment. PAM was able to induce cell death 29% higher than direct treatment as measured after 48 h. The depth of the growth medium is also one of the factors in the induction of apoptosis of cancer cells. The growth medium protected the cells from plasma exposure. The result shows that the low level (0 mm) of growth medium will cause more cell death as compared with the high level (2 mm) of growth medium. Apoptotic behavior of skin cancer cells was deduced from the fact that treated cells initially grew and died 12 h following the treatment, while untreated cells continued to grow and proliferate.