To determine the incidence and morphologic features of acute vascular rejection (AVR) in cardiac transplant patients who have not received OKT3 induction therapy, we performed immunofluorescence (IF) staining for Clq and C3c on 341 endomyocardial biopsies from 135 patients. Each AVR biopsy, defined by positive IF, was further evaluated for C4c, C5, IgG, IgM, and IgA. Light and electron microscopy were also performed. The clinical features of each case were reviewed. A total of 29 biopsies from 6 recently transplanted patients (1993) and 10 biopsies from 4 long-term transplants (pre-1993) had IF evidence of AVR. All patients with AVR had linear vascular deposits of various complement components and immunoglobulins. Of the 6 recently transplanted patients, 4 were multiparous females. The male had a single episode of AVR. IF patterns were variable between and within patients. Clq and C3c were the most consistently detected complement components. IgM was the most frequently detected antibody. Of the 10 cases of AVR, 6 occurred within the first month post-transplant. Myocyte necrosis was present in all cases with cardiac dysfunction. Patients with early onset AVR had more recurrences and one fatality. There was one fatality in the long-term transplant group. Concomitant grades 0 to 4+ cellular rejection did not correlate with results of IF or clinical severity. The incidence of AVR in non-OKT3-treated patients is 7%. Of the early onset patients, 66% are multiparous females, indicating the possible importance of prior sensitization. IF patterns are not predictive of outcome. AVR may be asymptomatic, but early onset predicts a difficult clinical course and is detected only by IF screening.