The binding of Cd(2+) to human serum transferrin in 0.1 M N-(2-hydroxyethyl) piperazine-N( ')-2-ethanesulfonic acid and 5 mM sodium bicarbonate at pH 7.4 has been studied by difference ultraviolet spectrophotometry. The apparent association constants were found to be 2.61 x 10(5) M( -1) and 8.51 x 10(4)M(- 1), respectively. These association constants are pH-dependent, reducing with both increasing and decreasing pH. The apparent pK(a) values were found to be 4.93 and 5.42. Competitive assays of binding of Cd(2+) to transferrin in the presence of citrate and human serum albumin at molar ratios corresponding to those found in normal plasma showed that a considerable amount of Cd(2+) was not bound to transferrin. The competitive binding assays indicate that approximately 50% of Cd(2+) is bound to transferrin, approximately 37% to albumin and reminder to citrate. These results therefore suggest that, although transferrin at pH 7.4 is the major Cd( 2+)-binding component of plasma, an appreciable amount of Cd(2+) may be bound to albumin.