ThinPrep (TP) and TriPath PREP (TriP) are two liquid-based cytologic preparations that produce a thin layer of cells. This study compares the diagnostic accuracy and different cytomorphologic alterations produced by these preparations in nongynecologic specimens. Samples from 10 urines (3 urothelial carcinomas and 7 negative), 4 positive serous fluids, and 7 fine-needle aspirates (FNAs) were prepared by both techniques. FNAs represented one each of: Hashimoto's thyroiditis (HT), hyperplastic colloid nodule (HCN), Hodgkin's lymphoma, liposarcoma, chondrosarcoma, squamous-cell carcinoma (SCC) metastatic to the lymph node, and carcinoid tumor. All 5 participants, none of whom had prior knowledge of the clinical history or histologic diagnosis, reviewed and interpreted the slides. Both techniques produced a clean background and were equally accurate in urines, serous fluids, and three FNAs. TriP was slightly more accurate in four FNAs: HCN and HT where colloid and lymphocytes were better represented, SCC where keratin and malignant cells were more readily identified among lymphocytes, and carcinoid which was easier to evaluate on TriP due to less cellular shrinkage and more dispersion of cells between aggregates. TP preparations had more cell shrinkage, and the chromatin was harder to evaluate. Both techniques produced artificial aggregations of lymphocytes, but TriP had a more evenly dispersed single-cell population between aggregates, rendering them easier to evaluate for atypia. TP produced fragmentation of large sheets that were flattened, while TriP contained larger branching sheets in a three-dimensional (3-D) configuration. TP produced a true monolayer of cells that were all spread at the same plane, while in TriP the cells were spread at slightly different planes, requiring frequent focusing of the viewed plane. While both techniques are acceptable for diagnostic purposes, they both introduce new cytomorphologic alterations that pathologists need to recognize. TriP seems superior to TP in FNAs specimens where preservation of architecture and cellular integrity are important considerations.