Introduction: Medical treatment with misoprostol represents one of the main treatments for Early Pregnancy Loss (EPL). In our study, we aimed to identify clinical features associated with a successful response to this approach. Methods: A prospective single-center observational study was conducted at the EPL Clinic of the Department of Obstetrics and Gynecology, Fondazione A. Gemelli IRCCS Rome, Italy. Patients were categorized according to the type of treatment received: spontaneous delivery, elective dilatation and curettage, or medical treatment. A separate analysis was performed within the medical treatment group to distinguish women with a successful response from those with an unsuccessful one. The success of medical treatment was calculated as the response rate (number of patients who successfully responded to treatment/total number of treated patients) with a 95% Confidence Interval (CI). For patients undergoing misoprostol treatment, a multivariable analysis was planned to identify predictors of a successful response, including variables with a p value less than 0.05 in the univariable analysis. Receiver Operating Characteristic (ROC) analysis was performed to evaluate the predictive ability of continuous obstetrics parameters for medical treatment success. The optimal cut-off value to differentiate responsive from unresponsive patients was also determined. The significance level was set at p < 0.05. Results: Sixty-four patients who underwent medical treatment were analyzed. Amenorrhea age was the only parameter inversely associated with treatment success, indicating that an earlier amenorrhea age correlated with a better response to misoprostol. ROC analysis identified a cut-off of 62.5 days, with an AUC (95% CI) of 0.72 (0.55–0.89). An amenorrhea age of ≤ 62.5 days predicted a successful response to medical treatment with a specificity (95% CI) of 90.0% (89.8–90.2) and sensitivity (95% CI) of 54.9% (41.2–68.6). Conclusions: Amenorrhea age emerged as a potential predictor of treatment response in women with EPL undergoing misoprostol therapy. However, further studies of larger sample sizes are needed to validate and improve our model.