In a prospective study of 21 hypertensive patients receiving hydralazine for 1 year, we found a close relationship between development of antibodies to deoxyribonucleoprotein (DNP) and to hydralazine but no evidence for cross-reactivity between antibodies to these two antigens. Of 8 patients who developed increased levels of antiDNP, 7 also developed antibodies to hydralazine. Inhibition of the reaction between DNP and antiDNP as measured by radioimmunoassay in 3 patients with hydralazine lupus could not be achieved with large amounts of hydralazine. However, antibodies to DNP produced in guinea pigs immunized with hydralazine conjugates could be inhibited with hydralazine in accordance with previous studies by others on rabbits. In the human, antibodies to DNP which develop during hydralazine administration are not due to cross-reactive antibodies nor do they appear as a result of immune response to an in vivo hydralazine DNP conjugate.