<p>Smooth endoplasmic reticulum aggregates (SERa<b>)</b> are a type of dysmorphism in oocytes derived from controlled ovarian stimulation (COS). The effect of SERa on assisted reproductive techniques (ART) outcomes is debatable. Based on some evidence, SERa-positive (SERa+) oocytes cause complications including newborn demise, and compromise the outcome of the unaffected oocytes of the same cycle. While other reports demonstrated equal developmental competence between SERa + and SERa-negative (SERa-) oocytes/cycles. We conducted a prospective cross-sectional study on 315 women candidates for ART and compared the outcome among SERa+ (<i>N</i> = 73) and SERa- cycles (<i>N</i> = 217). Furthermore, for the first time, we investigated the prevalence of SERa + cycles in women with various infertility etiologies. Our results indicated that SERa + patients presented higher levels of Estradiol on the day of ovulation triggering (<i>p</i> = 0.02). Regarding the ART outcome, there were no differences in the number of retrieved oocytes, oocyte maturation and fertilization rates among the groups. However, the quality of the unaffected oocytes (<i>p</i> = 0.03), the rates of day-3 top-quality embryos (<i>p</i> = 0.01, and <i>p</i> = 0.03 for grades A and B, respectively), and clinical pregnancy (<i>p</i> = 0.05) in SERa + group were significantly reduced. Moreover, the prevalence of SERa + cycles gradually increased among endometriosis, POI/POR, PCOS, normal women, tubal factor, and idiopathic groups. Our study suggests that suboptimal situations such as elevated levels of Estradiol can increase the occurrence of SERa + oocytes. This suboptimal phenomenon can negatively influence the outcome of the cycle. Thus, optimization of COS, particularly in vulnerable groups such as women with idiopathic infertility may lower the SERa + cycle occurrence, improving the ART outcome.</p>