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<strong class="journal-contentHeaderColor">Abstract.</strong> This study presents a comprehensive laboratory and field-based evaluation of dimethyl sulfoxide (DMSO) as a non-flammable working fluid for condensation particle counters (CPCs), directly compared to a butanol-operated counterpart across a wide range of pressures, temperatures, and aerosol types. Modifications to the instrument’s automatic refilling system ensured reliable operation over six months. Particle growth in the DMSO-CPC is strongly depending on the saturator temperature <em>T</em><sub>sat</sub> and the temperature difference Δ<em>T</em> between saturator and condenser, with optimal growth achieved at high <em>T</em><sub>sat</sub> and large Δ<em>T</em> values. Measurements with an optical particle counter downstream of the condenser, along with saturation and droplet size simulations, confirmed these trends and emphasized the importance of CPC internal settings for reliable particle growth. The DMSO-CPC achieved counting efficiencies and cutoff diameters comparable to the Butanol-CPC. The mean cutoff diameter was (5.8 ± 0.9) nm for the DMSO-CPC and (5.6 ± 0.5) nm for the Butanol-CPC. At the same time, the DMSO-CPC substantially reduced working fluid consumption and enabled stable long-term operation. The use of DMSO–H<sub>2</sub>O mixtures further extended the operational range and improved safety, making the CPC suitable for airborne measurements and remote monitoring. Recommendations regarding instrument modification, operational conditions, and hardware adjustments are made for operating a DMSO-CPC to gain results comparable to a Butanol-CPC. Overall, DMSO-based CPCs provide safe, efficient, and regulation-compliant operation without compromising measurement quality under challenging environmental conditions.