Background: Evaluation of patients with skin or subcutaneous nodules, especially if it was multiple represents a major problem for the clinicians. But with full investigations, the problem becomes easier. However, the final diagnosis depends on pathological reports of tissue biopsy [1]. The easy access of the skin nodule provides the soil for performance fine needle aspiration cytology and taking the samples by the pathologists, or the clinicians. Smear cytology gives many defaults[2]. Performance of cell blocks was a trial to avoid these defaults and improve the diagnosis. The results of smear and cell block examinations were compared with examination of tissue biopsies. Methodology: Two hundred twenty five skin and subcutaneous nodules from 225 patients underwent the material of this study. The patients were selected from those referred topathology department, faculty of medicine Zagazig University, through the period between January 2018 and December 2020. Fine needle aspirations were performed utilizing the ordinary 22-gaugeneedle 10 cc syringes. Cell blocks were done utilizing the remnants in the syringe after performance of the smears. Histopathological examination was done using biopsies taken later on. Results: According to tissue biopsy examination: Benign lesions constitute the commonest findings (180 cases) 80% 0f cases: Lipoma35 cases (15.5%), Adipose tissue30 cases (13.3%), Fibrolipoma 20 cases (8.8%), Fibroma20 cases (8.8%), Juvenile fibroma 5 cases (2.2%), Neurofibroma 5 cases (2.2%), Sebaceous cyst in 25 cases (11.1%), Implantation cyst, or dermoid cyst 20 cases (8.8%), Pilomatrixoma 5 cases (2.2%), Seborrheic keratosis 10 cases (4.4%), Madura foot (actinomycosis) 5 cases (2.2%). Intermediate lesions: Atypical lipoma 5 cases (2.2%). Malignant lesions 25 cases (11.11%): Basal cell carcinoma10 cases (4.4%), squamous cell carcinoma 10 cases (4.4%), Basosquamous cell carcinoma 5cases (2.2%). For the FNAC smear examination, the sensitivity test was: 83.01%, the specificity test was: 16.66%. For the cell blocks examination, the sensitivity test was: 97.77%, specificity test was: 100%. Conclusion: Smear cytology is an easy, rapid test for diagnosis of skin nodule and performance of cell blocks improves its sensitivity and specificity outcome, but both must be attempted, because smear may be inefficient for some cases while cell block cannot be performed others.