OBJECTIVE Hyperhomocysteinaemia is an independent risk factor for cardiovascular disease. We explored possible determinants of plasma homocysteine and cysteine concentrations amongst middle-aged and elderly subjects. METHODS Of 501 35-95-year-old randomly selected residents of Lund and Malmö, Sweden, 244 (49%; 131 men, 113 women) were investigated. RESULTS Total plasma homocysteine concentrations were higher in men than in women (mean +/- SD: 13.9 +/- 4.1 and 12.3 +/- 4.1 mumol L-1; P < 0.001), increased markedly with age (Spearman's rho = 0.488; P < 0.001), and were correlated (P < 0.001) to concentrations of blood folate, serum vitamin B12, and serum creatine (rho = -0.366, -0.338, and 0.463). Users of multivitamins had lower homocysteine levels than nonusers [10.5 +/- 3.3 mumol L-1 (n = 31) and 13.5 +/- 4.2 mumol L-1 (n = 213), respectively; P < 0.001]. Total plasma cysteine concentrations also increased significantly with age and increasing serum creatinine, but were unrelated to gender, blood folate, serum vitamin B12 and use of multivitamins. CONCLUSIONS Age, gender, folate, serum vitamin B12, serum creatinine and multivitamin usage are all important determinants of the plasma homocysteine concentration, whereas only age and serum creatinine are determinants of the plasma cysteine concentration. The age-related increase in homocysteine and cysteine may be linked to the age-related impairment of renal function, whereas the sex difference in plasma homocysteine may be because of the fact that more homocysteine is formed in men than in women in conjunction with creatine-creatinine synthesis.