Cryobiopsy has emerged in recent years as a tool of growing interest in the diagnosis of non-small cell lung cancer (NSCLC). We first conducted the study with the primary objective to compare the quality of cryobiopsies versus conventional forceps biopsies, including diagnostic yield and the feasibility of histological characterization and molecular testing, of malignant pleural effusion (MPE). Prospective study including 14 caucasian patients with MPE due to NSCLC who underwent semirigid pleuroscopy with cryobiopsies. The median biopsy size for conventional flexible forceps and cryoprobe was 2.5 mm (1.5-3.2 mm) and 5.5 mm (3.8-7.6 mm), respectively (p = 0.07). The number of biopsies also differed: flexible forceps: 5 (4-6.25) biopsies vs cryoprobe: 3 (3-4) biopsies(p = 0.01). The tumor/non-tumor ratio in the conventional forceps sample was 2.4 (1.2-5.9), while in the cryoprobe sample, it was 3.6 (1.2-10) (p = 0.09). Only in one case, the samples obtained during semirigid pleuroscopy were insufficient for molecular diagnosis. The incorporation of cryobiopsy into semirigid pleuroscopy has been demostrated to be a effective and safe diagnostic tool. This technique could shortening procedure time and facilitating tissue collection without increasing procedural risks.