Objectives: The primary aim of this study was to improve the diagnosis of lymphocytic pleural effusions (LPEs) by combining their ultrasound characteristics with their macroscopic and biochemical features. Methods: This prospective, single-center, clinical observational study was conducted over a period of three years. The possible malignant etiology of LPEs was assessed using several diagnostic criteria: 1. ultrasound characteristics of the LPEs; 2. typical combinations of macroscopic and ultrasound features; and 3. the logistic regression method with three parameters—pleural nodularity, absence of fibrin, and serum protein concentration. Results: Eighty-four patients with LPEs were included in this study. Pleural nodularity (first criterion) was an ultrasound characteristic that yielded the best individual results (p < 0.001) in the differentiation of malignant and nonmalignant etiologies of LPEs (accuracy 73.81%). The combination of the second and third criteria yielded the best results in the prediction of a malignant etiology of LPEs (sensitivity 90.48%, specificity 83.33%, PPV 84.44%, NPV 89.74%, accuracy 86.90%). Based on the results of this prospective study, a protocol for the diagnostic procedure of lymphocytic pleural effusions without a definitive fluid diagnosis has been proposed. Conclusions: A combination of the ultrasound characteristics of LPEs and their macroscopic and biochemical features has improved the predictive accuracy for the malignant etiology of LPEs.