Background: The pulse wave transit time (PWTT) increases with decreased vascular tone resulting from sympathetic blockade caused by regional anesthesia. It oscillates, exhibiting variability due to the interaction between the autonomic nervous and cardiovascular systems. We hypothesized that interscalene brachial plexus block (ISBPB) placement increases the PWTT and reduces the low-frequency power of PWTT variability (LF). Methods: Fifty-six patients receiving an ISBPB were analyzed. The PWTT was defined as the difference in milliseconds (ms) between the R peak of the electrocardiogram and the peak of the second-derivative photoplethysmographic waveform. The LF was calculated by integrating from 0.04 to 0.15 Hz on the power spectrum obtained from fast Fourier transform. The two variables were collected during the 5 min before the end of acclimatization (baseline), between 5 and 10 min after block needle insertion, and between 15 and 20 min after block needle insertion. Results: The PWTT increased significantly (P < 0.001) from baseline (mean [SD]: 155.3 [16.7] ms) to 5–10 min post-needle insertion (166.9 [15.4] ms) (mean difference [MD]: 11.6, 95% CI [9.2–14.0], P < 0.001) and 15–20 min post-needle insertion (165.6 [16.1] ms) (MD: 10.3, 95% CI [7.3–13.2], P < 0.001). The natural log-transformed LF (lnLF) decreased significantly (P < 0.01) from baseline (1.539 [0.560] ln[ms2/Hz]) to 5–10 min post-needle insertion (1.341 [0.617] ln[ms2/Hz]) (MD: –0.198, 95% CI [–0.356 to –0.040], P < 0.01) and 15–20 min post-needle insertion (1.396 [0.548] ln[ms2/Hz]) (MD: –0.144, 95% CI [–0.274 to –0.013], P = 0.03). Conclusions The post-ISBPB decrease in lnLF and increase in PWTT may be attributable to ISBPB-induced sympathectomy.