The future of rapid point-of-care diagnostics depends on the development of cheap, noncomplex, and easily integrated systems to analyze biological samples directly from the patient (e.g. blood, urine, and saliva). A key concern in diagnostic biosensing is signal differentiation between non-specifically bound material and the specific capture of target molecules. This is a particular challenge for optical detection devices in analyzing complex biological samples. Here we demonstrate a porous silicon (PSi) label-free optical biosensor that has intrinsic size-exclusion filtering capabilities which enhances signal differentiation. We present the first demonstration of highly repeatable, specific detection of immunoglobulin G (IgG) in serum and whole blood samples over a typical physiological range using the PSi material as both a biosensor substrate and filter.