VGX-3100 Delivered Intramuscularly (IM) Followed by Electroporation (EP) for the Treatment of HPV-16 and/or HPV-18 Related Anal or Anal/Peri-Anal, High Grade Squamous Intraepithelial Lesion (HSIL) in Individuals Seronegative for Human Immunodeficiency Virus (HIV)-1/2

Inclusion Criteria:

* Negative screening test for HIV-1/2 within 30 days of Dose 1;
* Confirmed anal or anal/peri-anal HPV-16/18 infection at Screening by polymerase chain reaction (PCR) from HSIL specimen;
* Anal tissue specimen/slides for diagnosis must be collected within 10 weeks of first dose of VGX-3100;
* At least one anal or anal/peri-anal (AIN2/3 and/or PAIN2/PAIN3) lesion that is histologically-confirmed as HSIL at Screening;
* Appropriate candidate for histology collection procedures (i.e. excision or biopsy) as judged by the Investigator;
* Female subjects must be post-menopausal, surgically sterile or agree to avoid pregnancy by continued abstinence or use of a contraceptive method with failure rate of less than 1% per year from Screening to one month after last dose of study medication (Week 12 or Week 40)
* Men who could father a child must agree to use at least one form of birth control during or continued abstinence from heterosexual intercourse prior to the study, for the duration of study participation and one month after last dose of study medication.
* Normal Screening electrocardiogram (ECG).

Exclusion Criteria:

* Untreated micro invasive or invasive cancer;
* Biopsy-proven Vaginal Intraepithelial Neoplasia (VAIN) and not undergoing medical care and/or treatment for VAIN;
* Biopsy-proven Vulvar Intraepithelial Neoplasia (VIN) and not undergoing medical care and/or treatment for VIN;
* Biopsy-proven Cervical Intraepithelial Neoplasia (CIN) 2/3 and not undergoing medical care and/or treatment for CIN;
* Biopsy-proven Penile Intraepithelial Neoplasia (PIN) and not undergoing medical care and/or treatment for PIN;
* Anal or anal/peri-anal HSIL that is not accessible for sampling by biopsy instrument;
* Intra-anal and/or peri-anal lesion(s) that cannot be fully visualized at Screening;
* Inability to have complete and satisfactory high resolution anoscopic exams (HRAs)
* Any treatment for anal or anal/peri-anal HSIL (e.g. surgery) within 4 weeks of Screening;
* Pregnant, breast feeding or considering becoming pregnant within one month following the last dose of study medication;
* Presence of any abnormal clinical laboratory values greater than Grade 1 per Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03 within 45 days prior to Day 0 or less than Grade 1 but deemed clinically significant by the Investigator;
* Immunosuppression as a result of underlying illness or treatment;
* History of previous therapeutic HPV vaccination;
* Receipt of any non-study related non-live vaccine within 2 weeks of any VGX-3100 dose;
* Receipt of any non-study related live vaccine (e.g. measles vaccine) within 4 weeks of any VGX-3100 dose;
* Significant acute or chronic medical illness that could be negatively impacted by the electroporation treated as deemed by the Investigator;
* Current or history of clinically significant, medically unstable disease which, in the judgment of the investigator, would jeopardize the safety of the subject, interfere with study assessments or endpoint evaluation, or otherwise impact the validity of the study results;
* Prior major surgery within 4 weeks of Day 0;
* Participation in an interventional study with an investigational compound or device within 4 weeks of signing the ICF;
* Any illness or condition that in the opinion of the Investigator may affect the safety of the subject or the evaluation of any study endpoint.