Objective A number of serum tumor markers have been investigated to aid clinicians in the differential diagnosis of ovarian masses. Serum C-reactive protein (CRP) is a widely used biomarker of inflammation and has been previously shown to be a promising biomarker in patients with ovarian cancer. Study design In a retrospective single-center study, we evaluated serum CRP in 576 patients with benign and in 242 patients with malignant (ovarian tumors of low malignant potential [LMP]: n = 44, epithelial ovarian cancer [EOC]: n = 198) ovarian masses. Results were correlated to clinical data. Results Median (25th, 75th percentiles) serum CRP in patients with benign ovarian tumors, with ovarian tumors of LMP, and with EOC were 0.5 (0.5, 0.6) mg/dL, 0.5 (0.5, 0.9) mg/dL, and 1.36 (0.5, 4.9) mg/dL, respectively ( p < 0.001). In the subgroup of patients with EOC, serum CRP significantly correlated with FIGO stage ( p < 0.001), residual tumor mass ( p < 0.001), and patients’ age ( p = 0.04), but not with tumor grade ( p = 0.2) and histologic type ( p = 0.4). In univariable and multivariable models including serum CRP, serum CA 125, and patients’ age, serum CRP independently predicted the presence of malignant ovarian masses ( p < 0.0001; Odds Ratio [OR] 5.3, 95% Confidence Interval [CI] 3.8–7.4). Serum CRP had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for identifying malignant ovarian masses of 49.8%, 84.1%, 57.1%, and 79.8%, respectively. Conclusion Serum CRP is associated with the presence of malignant ovarian tumors independent of serum CA 125 and patients’ age and can therefore be used as additional diagnostic marker in the differential diagnosis of ovarian masses.