Chromaffin granule transmitters such as chromogranin A and catecholamines have been used in the diagnosis of pheochromocytoma, but the diagnostic and prognostic value of chromogranin A have not been explored in malignant pheochromocytoma. We evaluated these transmitters in patients with pheochromocytoma (n=27), both benign (n=13) and malignant (n=14). Patients with benign pheochromocytoma were studied before and after surgical excision (n=6), whereas patients with malignant pheochromocytoma were evaluated before and after combination chemotherapy with regular cycles of cyclophosphamide/dacarbazine/vincristine (nonrandomized trial in n=9). During treatment, patient responses to chemotherapy were divided according to anatomic and clinical criteria: responders (n=5) versus nonresponders (n=4). Plasma chromogranin A rose progressively (P<0.0001) from control subjects (48.0+/-3.0 ng/mL) to benign pheochromocytoma (188+/-40.5 ng/mL) to malignant pheochromocytoma (2932+/-960 ng/mL). Parallel changes were seen for plasma norepinephrine (P<0.0001), though plasma epinephrine was actually lower in malignant than benign pheochromocytoma (P=0.0182). In bivariate analyses, chromogranin A, norepinephrine, and epinephrine discriminated between pheochromocytoma and control subjects (all P<0.0001), whereas in a multivariate analyses, norepinephrine was the best discriminator (P:=0.011). Chromogranin A was significantly different in benign versus malignant pheochromocytoma on both bivariate (P=0.0003) and multivariate (P:=0.011) analyses. After excision of benign pheochromocytoma, chromogranin A (P=0.028), norepinephrine (P=0.047), and epinephrine (P=0.037) all fell to values near normal. During chemotherapy of malignant pheochromocytoma (n=9), plasma chromogranin A (P=0.047) and norepinephrine (P=0.02) fell but not epinephrine. In 5 responders to chemotherapy, there were significant declines in chromogranin A (P=0.03) and norepinephrine (P=0.03) but not epinephrine; in 4 nonresponders, none of the transmitters changed. Plasma chromogranin A varied longitudinally with tumor response and relapse. We conclude that plasma chromogranin A is an effective tool in the diagnosis of pheochromocytoma, and markedly elevated chromogranin A may point to malignant pheochromocytoma. During chemotherapy of malignant pheochromocytoma, chromogranin A can be used to gauge tumor response and relapse.