<h3>Purpose/Objective(s)</h3> Achieving optimal tumor dose while minimizing organ at risk (OAR) uptake is a critical challenge for targeted radionuclide therapy (TRT), due to highly variable tumor uptake and biodistribution from patient to patient. Moreover, TRT is delivered using a standard dosing regimen for all patients, without knowledge if an ablative tumor dose, or critical OAR dose, has been reached. This potentially compromises outcomes that could be addressed by modulating the administered dose. SPECT-based dosimetry provides a snap-shot of body-wide dose distribution, but it is generally limited in availability and to a single time point. Therefore, methods for obtaining the total integrated dose for all patients are critically needed. A highly sensitive <i>in vivo</i> microdosimeter (IVµD) implanted within the tumor and OAR via biopsy needle solves this problem by monitoring the dose within the body in real time. Here, we demonstrate the world's first sub-mm<sup>3</sup> single charged particle sensitive IVµD and its applicability to Lu<sup>177</sup>-based TRT. The low power consumption (<0.6 mW) and miniaturized form factor (0.27 mm<sup>3</sup>) are compatible with <i>in vivo</i> implantation for continuous monitoring of TRT delivery and personalized dosing. <h3>Materials/Methods</h3> To achieve single particle detection, an array of ultra-small (1 µm<sup>2</sup>) diodes are integrated with in-pixel amplifiers on a 0.9 mm<sup>2</sup> integrated circuit. For each emitted beta-particle that intersects the chip, ∼1/3 of the deposited energy in the diode's depletion region creates electron-hole pairs. The generated electrons are then integrated on the diode's parasitic capacitor (C<sub>p</sub>). Because the amplitude of the voltage signal, V<sub>p</sub>, is inversely proportional to C<sub>p</sub>, a nearly minimum size diode (1 µm<sup>2</sup>, with C<sub>p</sub> = 2.4 fF) maximizes V<sub>p</sub> from the single hit. The diodes are arranged in a 64 ⨉ 64 array, providing a total detection area of 512 ⨉ 512 µm<sup>2</sup> in a monolithic silicon chip-let. Lu<sup>177</sup> is diluted to 10 different concentrations ranging from 1.5 ⨉ 10<sup>−3</sup>∼1.2 µCi/µL, equivalent to 0.18∼146 %ID/g assuming 800 µCi of injection, matching and exceeding the therapeutic dose range of 0.97∼649 Gy. The device is submerged in the tube and measures the activity of each solution for more than 40 minutes. <h3>Results</h3> The measured counts per minute (CPM) is highly proportional to the concentration over a wide range without saturation. The least square linear regression relationship between the measured CPM and concentration is CPM = 1290 ⨉ concentration (in µCi/µL), and highly linear with an R<sup>2</sup> value of 0.9998. The measured mean and the standard error of CPM ranges from 1.9 ± 0.8 CPM (at 1.5 ⨉ 10<sup>−3</sup> µCi/µL, or 0.18 %ID/g) to 1510 ± 46 CPM (at 1.2 µCi/µL, or 146 %ID/g), demonstrating the wide dynamic range necessary to measure low uptake organs at risk and high uptake tumors. <h3>Conclusion</h3> A sub-mm<sup>3</sup> diode based IVµD capable of detecting single beta-particles in real-time was demonstrated using solutions of Lu<sup>177</sup>. We envision that such a device can be used to optimize TRT dosing on a per-patient level improving clinical outcomes.