To elucidate whether mild rejection requires treatment, we retrospectively examined the spontaneous natural history of this histologic feature without an increase of immunosuppression. During a 4-year period, 55 heart transplantations were performed in 54 patients on whom 958 endomyocardial biopsies were performed. Among these biopsies, 162 specimens showed features of mild rejection. We studied the results of subsequent biopsies performed 7 to 10 days later, without any change in immunosuppression. These revealed regression of lesions to minimal rejection in 51 cases (31%), the same histologic feature in 82 cases (51%), or progression to moderate or severe rejection in 29 cases (18%). In 82% of these cases, therefore, no aggravation of histologic feature was observed. We separated the cases in which current-study biopsies showed mild rejection into three groups according to the result of the most recent biopsy, that is, minimal, mild, or moderate-severe rejection. The percentage of good outcome was not modified by the nature of the previous biopsy specimen: 84%, if minimal rejection was preceding the study biopsy; 82%, in the cases of mild rejection; and 77%, for moderate or severe rejection. We did not find significant differences in this evolution between patients with fewer or more than two moderate or severe acute rejections in the first 4-month period after heart transplantation (respectively, 15% or 24% progression to moderate or severe acute rejection after nontreated mild rejection).(ABSTRACT TRUNCATED AT 250 WORDS)