Purpose: To investigate the impact of pseudoexfoliation (PEX) syndrome on intraoperative phacoemulsification (PHACO) parameters and assess the economic cost of PHACO surgery for cataracts in patients with and without PEX syndrome. Methods: This was a retrospective quality register study on 5889 patients (6236 eyes) who underwent PHACO cataract surgery in the Eye Clinic, Clinical Hospital Centre Split, Croatia, over a 7-year period (May 2015 to December 2022), in accordance with the Guidelines of the Helsinki Declaration and approval from the Research Ethics Committee of the University Hospital Centre Split, Croatia. Inclusion criteria were patients with either presenile or senile cataract or cataract related to PEX syndrome who undertook PHACO procedure by the same experienced surgeon using the same PHACO device (Infiniti Vision System, Alcon Laboratories, Inc., Fort Worth, TX, USA). Eyes were categorized according to PEX presence- (PEX group) or absence (Group without PEX). The following recorded data about intraoperative PHACO parameters were collected: Cumulative Dissipated Energy (CDE), Ultrasound total time, PHACO time, torsional time, aspiration time, estimated fluid used, and duration of the surgical procedure. In the economic analysis, all PHACO parameters were considered, with a specific focus on the duration of the surgical procedure, costs associated with additional medical materials and devices, complications during surgery, and surgery procedure Diagnosis-Related Group (DRG) codes. Results: A total of 4535 cases were eligible for inclusion in the study, 278 (6.13%) were diagnosed with PEX and 4257 (93.87%) had no PEX. Significantly higher PHACO parameters were observed in the PEX group. Similarly, a statistically significant increase in the values of all PHACO parameters was observed with the increase in nuclear lens density. Intraoperative complications were more frequent in the PEX group. Zonular weakness requiring the use of a capsular tension ring (CTR) and posterior capsular rupture occurred 30 and 13 times more often, respectively, in the PEX group. The expected cost of the PHACO procedure was found to be 1.4 times higher in patients with PEX, compared to those without PEX, for all types of nuclear cataract. Conclusions: All PHACO parameters are significantly higher in patients with PEX. The costs associated with PHACO surgery for cataracts are greater for patients with PEX and are not covered by the present DRG codes, which highlights the need to accordingly adjust the DRGs for PHACO procedures in PEX patients, in order to maintain the quality of healthcare provided for these vulnerable patients.