Abstract Background and Aims Volume overload (VO) represents the main risk factor for cardiovascular death in peritoneal dialysis (PD) patients. The lack of objective methods and validated markers constitutes the basis for the high prevalence, which is one of the main causes of technique failure. The use of lung ultrasound, VExUS score and serum CA-125 (SeCA-135), has emerged to assess volume in heart failure patients. In this pilot study, we explored the association of these novel approaches with classical markers of VO Method A cross-sectional cohort study was conducted on fourteen PD outpatients, in which volume status was simultaneously assessed through SeCA-125 levels along with standardized 28-site lung ultrasound, VExUS Score (excluding renal Doppler), NT-proBNP levels, and bioimpedance spectroscopy (BIS). Clinical and physical examination parameters were collected simultaneously, and echocardiographic measures were collected from the clinical history in the previous 6 months. The inclusion criteria were: patients over 18 years old, in a PD program for at least 6 months, with good adherence to the technique. The exclusion criteria were: cardiovascular event in the three months prior to the study initiation, active uncontrolled neoplastic disease, or active infection or intercurrent illness in the 2 months prior to evaluation. Because NT-ProBNP does not follow the normal distribution, we used the Ig transformation (LgNT-proBNP) in the statistical process. Results The mean age was 68.9 ± 14.9 years, with an average of 29.9 ± 19.61 months on dialysis, a mean residual diuresis of 1.22 ± 0.88 liters, and the mean weekly KT/V was 2.10 ± 0.63. 28.6% of the patients have Congestive Heart Failure, 57.1% have Diabetes Mellitus and 100% have hypertension. The patients had a mean Charlson Index of 5.7 ± 2.1 and were using an average of 2.4 ± 1.1 antihypertensive drugs. 28.6% of the patients presented dyspnea, 14.3% had pulmonary crackles, and 35.7% had peripheral edema. Mean ECW/TBW was 0.48 ± 0.02, and overhydration by BIS was 1.18 ± 1.46 L. The mean number of B-lines was 8.79 ± 6.43, Se-CA-125 was 20.42 ± 8.66 IU/mL, and NT-proBNP was 3950 (172-35,000) ng/L. SeCA125 was positively associated with left atrial volume (r = 0.823, p = 0.01), estimated PASP (r = 0.787, p = 0.03), LogNT-proBNP (r = 0.614, p = 0.02) and negatively correlated with TAPSE (r = −0.77, p = 0.05). Likewise, LogNT-proBNP was positively associated with CRP (r = 0.54, p = 0.05), and ECW/TBW ratio (r = 0.57, p = 0.03) and negatively correlated with albumin (r = −0.66, p = 0.01). There was no correlation between the number of B-lines and Se-CA-125 with the diameter or collapsibility of the IVC, pulsatility portal vein, or analysis of Doppler hepatic vein, VExUs grade, ECW/TBW ratio, NT-proBNP levels, renal residual function or the presence of edema or pulmonary crackles. Patients with overhydration by BIS (>7.5% OH/TBW) showed more B-lines (13 ± 6.32 vs. 5.57 ± 5.028 p = 0.04). Patients diagnosed as overloaded by B-lines (>5 lines) did not show a higher level of SeCA-125 (22.2 ± 9.50 vs 16 ± 4.16; p > 0.05), VCI diameter (1.6 ± 9.43 vs 2 ± 0.27; p > 0.05), OH/TBW ratio (8.4 ± 8.55 vs 2.55 ± 4.13; p > 0.05) or Log NT-proBNP (0.91 ± 0.76 vs 3.19 ± 0.91; p > 0.05). Conclusion The number of B-lines in lung ultrasound can detect patients with VO earlier compared to BIS. SeCA-125 levels are sensitive to changes in the echocardiogram. The use of both methods can help us detect early signs of volume overload in peritoneal dialysis patients.