Background Although electroconvulsive therapy (ECT) in major depression is effective, cognitive effects limit its use. Reducing the width of the electrical pulse and by using the right unilateral electrode placement may decrease adverse cognitive effects, while preserving efficacy. Methods In a double-masked study, we randomly assigned 90 depressed patients to right unilateral ECT at 6 times seizure threshold or bilateral ECT at 2.5 times seizure threshold, using either a traditional brief pulse (1.5 milliseconds) or an ultrabrief pulse (0.3 millisecond). Depressive symptoms and cognition were assessed before, during, and immediately, 2, and 6 months after therapy. Patients who responded were monitored for a 1-year period. Results The final remission rate for ultrabrief bilateral ECT was 35%, compared with 73% for ultrabrief unilateral ECT, 65% for standard pulse width bilateral ECT, and 59% for standard pulse width unilateral ECT (all P < .05 after covariate adjustment). The ultrabrief right unilateral group had less severe cognitive side effects than the other three groups in virtually all primary outcome measures assessed in the acute postictal period, and during and immediately after therapy. Both the ultrabrief stimulus and right unilateral electrode placement produced less short- and long-term retrograde amnesia. Patients rated their memory deficits as less severe after ultrabrief right unilateral ECT compared with each of the other three conditions (P < .001). Conclusions The use of an ultrabrief stimulus markedly reduces adverse cognitive effects, and when coupled with markedly suprathreshold right unilateral ECT, also preserves efficacy. (ClinicalTrials.gov number, NCT00487500.)