This report demonstrates that smoking is a major factor of nonspecific elevation of the tumor marker placental-like alkaline phosphatase (PLAP). In 98 healthy nonsmokers the mean of the enzyme activity was determined as 0.068 U/L (range, +/- 2 SD 0-0.144 U/L) compared to a mean of 0.378 U/L (range, +/- 2 SD 0-1.02 U/L) in 65 smokers. In view of this finding the usefulness of PLAP as a tumor marker was re-evaluated in 286 patients with various neoplasms and a negative smoking history. Of these patients, 23% and 50% had elevated values for PLAP and carcinoembryonic antigen, respectively. When compared to the range of PLAP in normal smokers only 4.1% of the patients showed elevated values. An increased incidence of elevated PLAP was found in patients with tumors of the lung, pancreas, stomach, colon/rectum, ovaries, and in 2 of 3 seminomas. It was concluded from the data that PLAP is a useful tumor marker for selected neoplasms provided its use is confined to nonsmokers.