Previous investigations have elucidated an erythrocyte lithium-sodium countertransport (LSC) system as the primary mechanism for extruding lithium from the cell, and this activity has been described in terms of Michaelis-Menten kinetics. In most clinical studies the maximum velocity (Vmax) of the LSC has been measured by estimating the rate of lithium efflux from lithium-loaded cells. To date, few studies have examined whether the affinity (Km) of the LSC for lithium might be altered in patients with affective disorders. In the present study we examined LSC kinetic parameters (Vmax, leak, Km, and in vitro lithium ratio) at baseline in 80 patients with affective disorder and 25 healthy control subjects, and after 6 weeks of lithium administration in 33 of the patients. No differences in Vmax were observed between any patient and control group, although Vmax was significantly lower in unipolar depressed men compared to bipolar men (P = 0.043). The affinity (Km) of the transport 'carrier' for lithium did not differentiate between patient and control groups. Chronic lithium administration caused a decreased Vmax in bipolar men (P = 0.015), an increase in the in vitro lithium ratio in bipolar men (P = 0.002) and bipolar women (P = 0.002), and a marginal increase in Km in bipolar men (P = 0.08) and bipolar women (P = 0.06). Although the present data do not demonstrate an underlying difference for Km between affectively ill patients and controls, they do indicate a decrease in the affinity of the transport 'carrier' for lithium after chronic lithium administration.