The development of a whole-column radiation detector for measurement and separation of low amounts of beta emitting analytes is described. The design of this detector is unique with all of the chromatography media located within the detector volume. This whole-column design provides the advantage of increased radiation signal without loss of chromatographic efficiency, which translates to increased detectability. This increase was compared theoretically with flow-through radiation detection, and the theory was tested experimentally. Using two analytes, carbon-11-labeled m-hydroxyephedrine and alpha-methylepinephrine, only 3 and 8 Bq (80 and 220 pCi), respectively, were needed to obtain a 10% coefficient of variation using whole-column detection. For [11C]-m-hydroxyephedrine, 100 times more radioactivity was required to achieve the same coefficient of variation using flow-through detection. A limit of detection (LD) for the analytes of 2 Bq (54 pCi) was obtained for whole-column detection, an improvement of 50 in LD compared with flow-through detection. Signal improvement increased linearly with the chromatographic resolution. The whole-column detection method is robust and applicable to many chromatographic separations.