BACKGROUND: Surgical site infection is defined as infection occurring within 30 days after surgery. It is recently reported that the specific time when the majority of surgical site infections would develop is a key to early detect the infection and to prevent and early interven against their pressing complications. Therefore, the current study aimed to determine the incidence, predictors and time to surgical site surgical site infection among general surgery patients at specialized hospitals in the Amhara region. METHOD: Institution-based prospective follow-up study was conducted at specialized hospitals in the Amhara region. Patients were followed up for a maximum of 30 postoperative days. Data were collected using Epicollect5 v 3.0.5 software. Inpatient follow-up and diagnosis were done by direct inspection of the wound while post-discharge was done by phone call follow. Data were analyzed using STATA™ version 14.0. Kaplan–Meier curve to estimate survival time and long rank test to compare survival curves were used. A life table was used to estimate the survival probability. Proportional hazard assumption and multicollinearity were checked and both were fulfilled. Predictors with a P-value < 0.05 in simple cox regression were included in the multiple cox regression. A P-value less than 0.05 was considered to be statistically significant. The exact partial likelihood method was used to handle tied events. RESULT: A cumulative incidence rate was 39.1% and the incidence density was 17.59 per 1000 person- day-observation. The incidence of post-discharge SSI was 70.3%. The cumulative probability of surgical patients surviving at the end of the follow-up (30 days) was 0.5914. The median survival time was undetermined. Because, the largest observed analysis time was censored. Being male (AHR: 1.98, 95% CI: 1.201 – 3.277, diabetes Mellitus (AHR: 1.819, 95% CI: 1.097 – 3.016), surgery history (AHR: 2.078, 95% CI: 1.345, 3.211), antimicrobial prophylaxis given 30 minutes to 1 hour prior to surgery (AHR: 2.60, 95% CI: 1.676, 4.039), American Society of Anesthesiologists score ≥ III AHR: 6.710, 95% CI: 4.108, 10.960), longer preoperative hospital stays (AHR: 1.007 95% CI: 1.002, 1.013), longer duration of the surgery (AHR: 1.035 95% CI: 1.001, 1.070), increased age (AHR: 1.022 95% CI: 1.000, 1.043), and ≥ 7 professionals in the OR (AHR: 1.085 95% CI: 1.037, 1.134) were found to be the predictors of SSI. CONCLUSION: The incidence of surgical site infection was higher than the acceptable international range. The majority of the SSIs occurred after hospital discharge and within 16 post-operative days. The main predictors of SSI were Age, Sex, DM, previous surgical history, the timing of Antimicrobial prophylaxis, ASA score, pre-operative hospital stay, duration of surgery, and the number of professionals in the OR. Hence, hospitals should consider implementing mechanisms, such as post-discharge surveillance, to capture post-discharge SSI, initiate early treatment, prevent pressing complications, and assess the impact of any prevention/improvement interventions. It is also critical to work against modifiable predictors and give special attention to high-risk patients, as they found in this study. KEYWORDS: SSI, General Surgery, time to development, Amhara region