Aphakic penetrating keratoplasty (APKP) and combined penetrating keratoplasty with lens extraction (CPKP) are highly successful surgical procedures, with clear corneas occurring in over 90% of cases. However, macular problems tend to develop or appear postoperatively, and visual acuity is disappointing, principally because of either cystoid macular edema (CME) or pre-existing macular degeneration. To determine whether vitreous manipulation at the time of surgery alters the macular outcome, 132 eyes were studied prospectively. Eighty-four of these had pre-existing aphakia and all underwent anterior vitrectomy at the time of APKP. Forty-eight eyes were planned for CPKP and were randomly assigned to one group that had anterior vitrectomy or to a second group that had no vitrectomy at the time of CPKP. The incidence of clinically significant and angiographically documented CME at six months postoperative was 35/84 (42%) in APKP eyes, 9/48 (19%) in CPKP eyes, 8/24 (33%) in CPKP eyes with vitrectomy, and 1/24 (4%) in CPKP eyes without vitrectomy. The data strongly suggest that transpupillary anterior vitrectomy at the time of penetrating keratoplasty, as compared with no vitreous manipulation at all, may contribute to a high incidence of postoperative persistent CME.