In previous studies, measuring the levels of calprotectin in patients with pleural effusion (PE) was an exceptionally accurate way to predict malignancy. Here, we evaluated a rapid method for the measurement of calprotectin levels as a useful parameter in the diagnosis of malignant pleural effusion (MPE) in order to minimise invasive diagnostic tests. Calprotectin levels were measured with Quantum Blue® sCAL (QB®sCAL) and compared with the gold standard reference ELISA method. Calprotectin levels in patients with benign pleural effusion (BPE) were significantly higher (p < 0.0001) than for MPE patients. We measured the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive and negative likelihood ratios (LRs) for a cut-off value of ≤ 14,150 ng/mL; the diagnostic accuracy was 64%. The odds ratio for PE calprotectin levels was 10.938 (95% CI [4.133 - 28.947]). The diagnostic performance of calprotectin concentration was better for predicting MPE compared to other individual parameters. Comparison of two assays showed a slope of 1.084, an intercept of 329.7, and a Pearson correlation coefficient of 0.798. The Bland-Altman test showed a positive bias for the QB®sCAL method compared to ELISA fCAL®. Clinical concordance between both these methods was 88.5% with a Cohen kappa index of 0.76 (95% CI [0.68 - 0.84]). We concluded that QB®sCAL is a fast, reliable, and non-invasive diagnostic tool for diagnosing MPE and represents an alternative to ELISA that could be implemented in medical emergencies.