Background: Primary unexplained recurrent pregnancy loss (URPL) remains a major reproductive health problem, and increasing evidence suggests that immune and inflammatory dysregulation may contribute to its pathogenesis.  Objective: To assess first-trimester maternal serum PTX3 levels in women with primary unexplained recurrent pregnancy loss and compare them with healthy pregnant controls, and to evaluate the potential diagnostic value of PTX3 in predicting URPL. Patients and Methods: This prospective case-control study was conducted at Tikrit Teaching Hospital, Iraq, from January 2024 to December 2024. Eighty pregnant women in the first trimester were enrolled and divided into two groups: 40 women with primary unexplained recurrent pregnancy loss and 40 healthy pregnant controls with at least one previous uncomplicated pregnancy. Women with known causes of recurrent miscarriage, smoking, multifetal pregnancy, hypertension, preeclampsia, intrauterine growth restriction, preterm birth, or intra-amniotic infection were excluded. Maternal venous blood samples were collected under aseptic conditions, and serum PTX3 levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: Maternal demographic and baseline clinical characteristics were comparable between the two groups, with no significant differences in maternal age, duration of marriage, height, weight, body mass index, socioeconomic status, residence, smoking status, or gestational age at sampling (p>0.05). In contrast, serum PTX3 levels were significantly higher in the URPL group than in controls (12.00 ± 4.07 vs. 1.69 ± 0.91 ng/mL, p<0.001). PTX3 levels also showed a progressive increase with the number of previous miscarriages, rising from 9.7 ± 2.8 ng/mL in women with three miscarriages to 14.7 ± 2.6 ng/mL in women with six or more miscarriages. Diagnostic analysis showed that a PTX3 cutoff value of 6.0 ng/mL provided the best balance between sensitivity (87.5%) and specificity (90.0%) for predicting URPL. Conclusions: First-trimester maternal serum PTX3 levels are significantly elevated in women with primary unexplained recurrent pregnancy loss and increase with miscarriage frequency. These findings support a possible role of PTX3 in the inflammatory and immune mechanisms underlying URPL and suggest that PTX3 may serve as a promising early biomarker for identifying women at increased risk.