It remains unclear whether physiologic differences exist in musculoskeletal ultrasound nerve measurements when comparing bilateral and unilateral carpal tunnel syndrome (CTS) patients. Similarly, the influence of body mass index on CTS severity is not well characterized. Unilateral and bilateral CTS patients were seen from October of 2014 to February of 2021. Obese and nonobese CTS patients were compared. Median nerve cross-sectional area (CSA), Boston Carpal Tunnel Syndrome Questionnaire (BCTSQ), and six-item Carpal Tunnel Symptom Score (CTS-6) measures were obtained. Nerve conduction studies recorded distal motor latency (DML) and distal sensory latency (DSL). Statistical analysis used Wilcoxon signed rank testing for paired continuous variables, Mann-Whitney U testing for nonpaired continuous variables, and chi-square testing for continuous variables, with a significance level of P < 0.05. A total of 109 (218 nerves) bilateral and 112 (112 nerves) unilateral CTS patients were reviewed. Bilateral patients had larger median nerve CSAs on their more symptomatic side, when defined by BCTSQ score ( P < 0.0001), CTS-6 score ( P < 0.0001), DML ( P < 0.0001), and DSL ( P < 0.01). Bilateral patients also had higher symptom severity scale ( P < 0.01) and DSL ( P < 0.001) outcomes compared with unilateral patients. Obese patients had higher median nerve CSA ( P < 0.01), prolonged DML, and prolonged DSL ( P < 0.0001) values despite similar CTS severity (BCTSQ and CTS-6). Ultrasound identifies the more symptomatic side in bilateral patients, which correlates with increasing severity (NCS and BCTSQ). Obesity increases median nerve CSA and prolongs nerve conduction studies without influencing CTS severity. This information can be used when considering which diagnostic test to order for CTS.