Background: Pleural effusions remain a common medical problem which often requires diagnostic pleurocentesis to determine the underlying cause. Pleurocentesis is a frequently performed procedure worldwide with improved safety using ultrasound (US) technology. Objectives: This prospective, single-center study evaluated the use of an ultraportable handheld (UPHH) US compared with standard point-of-care (SPOC) US in determining a safe site for pleurocentesis. In addition, US image quality and factors impacting on image quality were assessed using both UPHH and SPOC US. Methods: Paired US assessments were performed by thoracic physicians using UPHH and SPOC US on patients with unilateral pleural effusions to determine a safe site for pleurocentesis (defined as >2 cm of pleural fluid, >2 cm from a solid organ/diaphragm, and <7 cm chest wall depth). Distance measurements for key structures and image quality scores (using a 5-point Likert rating scale) were obtained at the time of US assessment. Factors affecting image quality were analyzed using univariate analysis. Results: In 52 of the 54 included patients (96.3%), UPHH US was able to identify a safe site for pleurocentesis. Distance measurements between UPHH and SPOC US were not statistically different (all <0.5 cm with values of p > 0.05), but image quality was reduced in UPHH compared with SPOC US by 1 point on a 5-point Likert rating scale (p < 0.002). Increasing body mass index was associated with a reduction in image quality in both UPHH and SPOC US (all p < 0.01). Conclusions: Although image quality was lower in UPHH than SPOC US, a safe site was found in 96.3% of patients, which suggests that UPHH US may be a useful tool for diagnostic pleurocentesis when SPOC US is not available (http://www.anzctr.org.au/, Australia New Zealand Clinical Trials Registry, No. ACTRN12618001592235).