Comprehensive interrogation of the cell surface proteome is critical for identifying targets for immunotherapy. Although surfaceomic technologies have advanced, current approaches remain limited by sensitivity and functional group specificity, restricting analyses to samples with large cell numbers and potentially overlooking subsets of surface proteins. To overcome these limitations, we developed Surfaceome Capture by Multiplex (SUCAM) biotinylation, a combinatorial strategy that employs multiplexed biotin reagents to derivatize multiple functional groups on cell surface proteins. Following enrichment with streptavidin magnetic beads, proteins were identified and quantified by LC–MS/MS. SUCAM enabled enhanced detection of plasma membrane and cell surface proteins compared with single-reagent methods, achieving robust identification from as few as 1.2 million cells. Replicate analyses demonstrated high reproducibility (mean coefficient of variation, 17%). Application of SUCAM to a panel of leukaemia cell lines recovered canonical leukaemic surface antigens as well as proteins with previously uncharacterised roles in this malignancy. These findings establish SUCAM as a complementary surfaceomic strategy that broadens proteome coverage and facilitates the discovery of therapeutic targets in both haematological and solid tumours.