Chronic lymphocytic Leukaemia (CLL) is a B-cell malignancy marked by biological heterogeneity, variable progression and survival outcomes. Orphan toll-like receptor CD180 (RP105) complexed with the accessory protein MD-1 and CD150, which belongs to the signalling lymphocyte activation molecule family (SLAMF1), have emerged as an important modulators of CLL cell signaling and fate. However, their functional interplay, remains insufficiently understood. This study investigated the surface and intracellular expression of CD180, CD150, and MD-1 in primary CLL cells and the MEC-1 cell line, alongside their downstream signaling responses. Flow cytometric analyses revealed that MD-1 expression is tightly associated with CD180 and CD150 positivity, which may further indicate a role for MD-1 in stabilizing CD180 surface localization. Stimulation of MD-1⁺CD180⁺ CLL cells revealed four distinct signaling phenotypes: AKT signalers, p38MAPK signalers, dual signalers, and non-responders. CD150low cells preferentially activated AKT, whereas CD150high cells favored p38MAPK signaling, indicating context-dependent modulation of downstream pathways. Notably, stimulation via CD150 alone induced phosphorylation of both AKT and p38MAPK in specific subsets, confirming its independent signaling capacity. In synchronized MEC-1 cells, CD180 and MD-1 expression peaked at 48 h, coinciding with enhanced AKT phosphorylation upon combined CD180/CD150 stimulation. These data suggest that the temporal dynamics of CD180 expression modulate the outcome of CD150-driven signaling, indicating a tightly regulated and interdependent interaction. Collectively, these findings define a CD180/MD-1/CD150 signaling axis that underlies the intracellular signaling heterogeneity in CLL. The relative expression balance between CD180 and CD150 may steer cells toward pro-survival or stress-associated signaling, providing novel mechanistic insight into CLL biology and identifying candidate biomarkers or therapeutic targets.