The premorbid level of selenoprotein P in plasma from subjects with cancer at different sites was compared with that from control subjects in a nested case-control study. A health screening of 12,500 middle-aged men was performed during 1974-1982 in Malmö, Sweden, and from the 400 cancer cases that were identified during follow-up until the end of 1988, 302 plasma samples were available for analysis of selenoprotein P. Two living controls per case of the same screening day and age were chosen. Selenoprotein P levels in subgroups of major cancer sites were lower in cases than in controls for the respiratory tract (1.20 and 1.30 arbitrary units, respectively; p < 0.05) cancer group. The odds ratio for overall cancer risk in the lowest quintile of selenoprotein P level compared with that in the highest was 5.2 [p (for trend) = 0.01]. In subgroups of major cancer sites, the odds ratios for cancer risk in the lowest tertile compared with the highest were 6.0 [p (for trend) = 0.004] in the respiratory tract and 3.4 [p (for trend) = 0.002] in the digestive tract. In cases + controls, selenoprotein P was lower in smokers than in nonsmokers (p < 0.05). Selenoprotein P was significantly correlated to plasma albumin, fasting blood glucose, and body mass index and inversely correlated to plasma alpha 1-antitrypsin and gamma-glutamyl transferase. The results suggest that a low plasma selenoprotein P level is associated with higher future risk of respiratory and digestive tract cancer in middle-aged men.