Disseminating cells of a primary solid tumor may represent the origin of metastases and relapses. We aimed at comparing the diagnostic efficacy of multicolor flow cytometry (MFC) and morphology/immunohistochemistry (IHC) in the detection of disseminated tumor cells in the bone marrow (BM) and body fluids of patients with solid tumors, and in pediatric neuroblastoma cases. We investigated 72 samples retrospecively from 50 patients by MFC. Morphology/IHC data were available in 48 cases. In the first cohort, 36 samples derived from 34 patients with various forms of suspected and proven solid tumors and in the second cohort, 36 samples of 16 children with suspected and proven neuroblastoma were analyzed at diagnosis or during follow-up in a 4-color setting by MFC, and the results were compared with those obtained by IHC. In the group of various solid tumors, we found 91% concordance between IHC and MFC, and it was 65% in the neuroblastoma group, and 77% overall. Detection of disseminated tumor cells was found to be more effective by MFC in de novo neuroblastoma samples (100% vs. 86%). The advantage of MFC was even more pronounced when minimal residual disease was evaluated (efficacy, 92% vs. 68%). In contrast, efficacy of IHC was 100% in the group of various solid tumors, whereas it was 91% for MFC. We conclude that MFC and IHC are both essential tools for examining infiltration of BM and body fluids by disseminating solid tumor cells. In the case of neuroblastoma, however, minimal residual disease detection by MFC in a hypoplastic/aplastic BM environment was more effective than IHC, as considerably more cells could be analyzed.