Abstract Purpose Posterior capsule opacification (PCO) is one of the most common complications of cataract surgery, and there is an urgent need to reduce its incidence. Its main treatment, neodymium:YAG (Nd:YAG) laser posterior capsulotomy, may be associated with significant morbidity and is expensive. In this study, the authors ascertain the effect of posterior chamber intraocular lens (PC-IOL) fixation and various IOL designs (rigid polymethyl methacrylate [PMMA] optic and small-incision foldable designs) on the pathogenesis of PCO. Design Prospective analysis of pseudophakic eyes obtained postmortem. Participants A total of 3493 eyes with PC-IOLs obtained postmortem and received between 1984 and 1998. Methods Miyake-Apple posterior photographic technique. Main outcome measures Peripheral Soemmering’s ring, central PCO in the visual axis, and eyes that have had Nd:YAG laser posterior capsulotomy were analyzed and scored, and these findings were correlated with the type of fixation and IOL design. Results The degree of formation of peripheral Soemmering’s ring was not influenced by IOL fixation. The acrylic design revealed relatively low Soemmering’s ring scores. In contrast, central PCO and Nd:YAG laser capsulotomy scores were consistently influenced by fixation. The scores were significantly lower in eyes with in-the-bag fixation. The bag-bag fixated acrylic-PMMA design and the three modern silicone IOL designs analyzed in this study had less central PCO and lower posterior capsulotomy scores than did the PMMA IOLs. Conclusions The formation of peripheral PCO (the Soemmering’s ring), the precursor of clinically significant, vision-threatening PCO, is not significantly influenced by the haptic fixation pattern. It is much more dependent on the quality and thoroughness of surgical cortical cleanup. Reduction of Soemmering’s ring is an important goal because the retained regenerative cortical cells within this lesion are the cells of origin of PCO. The acrylic IOL design was associated with a lessor amount of peripheral Soemmering’s ring as compared with all other designs. In sharp contrast to peripheral PCO, fixation of the IOL was a highly significant factor affecting the formation and quantity of central PCO—the clinically significant opacity behind the IOL optic, measured in this series either by scoring an intact retro-optical membrane or by documenting the presence of a Nd:YAG laser posterior capsulotomy orifice. The quantity of central PCO was consistently much lower in eyes with in-the-bag fixated IOLs compared with lenses with one or both haptics out of the bag. This is best explained by the fact that secure in-the-bag fixation positions the IOL optic in the best possible position to create a barrier effect. The lowest PCO rates were generally noted with the acrylic and modern silicone IOL designs.