The impact of several differentially functionalized SWCNTs, including pristine, unfunctionalized CNTs (U-CNTs) and differentially carboxy-functionalized CNTs (CNT-30, CNT-40 and CNT-50) on degranulation and histamine release of a model mast cell line (RBL-2H3 cells) was investigated. Greater declines in cell viability at 24h were noted when cells were exposed to U-CNTs (78.5 ± 3%) compared to CNT-30 (55.4 ± 4%), CNT-40 (58.4 ± 3%) and CNT-50 (55.8 ± 4%). U-CNT exposure caused a significantly greater decline in IgE-FcεRI-mediated degranulation compared to acid functionalized CNT-30 at all concentrations tested. Importantly, removal of U-CNTs resulted in recovery degranulatory function while no recovery was found in cells exposed to CNT-30. U-CNT exposure resulted in a concomitant reduction in MAPK/ERK activation at 2 h declining to 53.0 ± 11% of control in the 250 mg L− 1 exposure group. However, similar to the degranulatory responses, MAPK/ERK activity could be rescued in RBL-2H3 cells exposed to U-CNTs but not in the AF-CNT exposures. Our results suggest that U-CNT result in reduced downstream activation of signaling kinases and suggests that the diminished degranulatory response observed after U-CNT exposure may result from a reduction in IgE-FcεRI aggregation.