There is considerable interest in the highly parallelized mass spectrometry analysis of complex sample mixtures without any time-consuming prepurification. Porous silicon-based laser desorption/ionization mass spectrometry (pSi LDI-MS) is enabling technology for such analysis. Previous studies have focused on pSi surface functionalization to enhance sensitivity of detection and engineer surfaces for sample capture and enrichment in LDI-MS analysis. In this report, we build on this work by showing that surface functionalization of thin pSi films can be extended to the covalent immobilization of antibodies, producing a porous immunoaffinity surface. We demonstrate highly selective mass spectrometric detection of illicit drugs (benzodiazepines) on pSi films displaying antibenzodiazepine antibodies covalently immobilized via isocyanate chemistry. The effects of antibody immobilization conditions, antibody concentration, and surface blocking on LDI-MS performance and selectivity were studied. X-ray photoelectron spectroscopy (XPS) was instrumental in characterizing surface chemistry and optimizing LDI-MS performance. Overall, our approach is suitable for rapid and sensitive confirmatory analysis in forensic toxicology requiring only minimal sample volume and may be applied to other areas requiring small molecular analysis such as metabolomics and pharmacology.