Purpose: The purpose of this study was to evaluate the effect of injection technique on the occurrence of local adverse events during implantation of hyaluronic acid gel particle fillers. Methodology: A prospective, controlled study randomly assigned 283 ethnically-diverse subjects with moderate-to-severe nasolabial folds (NLFs) and marionette lines to receive midface injections of one of two lightly-crosslinked hyaluronic gel fillers: RestylaneŽ (smaller gel particles) or PerlaneŽ (larger gel particles). Investigators could use different injection techniques for this study. Touch up treatments were allowed at 2 weeks. Subjects were assessed for local adverse events (e.g., erythema, ecchymosis, edema, itching, pain, tenderness) at 72 hours and at 2, 6, 12, and 24 weeks. Data collected included physician experience, time taken to correct a specific wrinkle (NLF or marionette line), depth of injection, volume used to correct a specific wrinkle, number of injection sessions required to correct a specific wrinkle (initial and/or +/- 2-week touch-up), investigator method of injection (linear threading [push or pull], multiple puncture, or use of fanning needle after dermal penetration). Per the statistical analysis plan, assessment variables were pre-assigned a correlate to the rate of local adverse events. Results: 282 subjects (Restylane, n=142; Perlane, n=141) were evaluated over the full study period; 1 was lost to follow-up. The rate of adverse events was not significant at any time point for: the number of sessions required to correct a specific wrinkle, years of physician experience, or Perlane vs. Restylane. Based upon these initial results, the remaining variables were evaluated using pooled data and logistic regression. Increased safety was significantly associated with the avoidance of fan-like injection, lower volumes per site, and slower injection technique (p<0.0001). Due to the linear relationship between volume and time and the interrelationship of their effect, volume/time was added to the logistic regression in order to assess the impact of flow on adverse reactions. Because flow was not directly measured, the analysis was restricted to flow rates below 1.4 mL/min, which prevented the masking of episodic high flows by overall long injection periods. Flow rates below 0.3 mL/min were found to significantly reduce local adverse events (odds ratio<0.3). Conclusions: The product safety profiles of two hyaluronic acid gel fillers (Restylane and Perlane) were identical. The number of sessions required to correct a specific wrinkle, years of physician experience did not affect the rate of adverse reactions. Injection technique (i.e., fan-like injection or use of high flow rates) that dissected the sub-epidermal plane increased the rate of local adverse events.