The aims of this study were to analyze the presence of gender differences in the phenotypic expression of schizophrenia at the onset of illness and to explore whether these differences determine clinical and functional outcome 2 years after the initiation of treatment. Data from 231 first-episode-psychosis non-substance-dependent patients (156 men and 75 women) participating in a large-scale naturalistic open-label trial with risperidone were recorded at inclusion and months 1, 6, 12, and 24. Men presented a significant earlier age of onset (24.89 years vs. 29.01 years in women), poorer premorbid functioning, and a higher presence of prodromal and baseline negative symptoms. Women were more frequently married or lived with their partner and children and more frequently presented acute stress during the year previous to onset than men. No other significant clinical or functional differences were detected at baseline. The mean dose of antipsychotic treatment was similar for both genders during the study, and no significant differences in UKU scores were found. The number of hospitalizations was similar between groups, and adherence was more frequent among women. At the 2-year follow-up, both groups obtained significant improvements in outcome measures: PANSS, CGI severity, and GAF scores. Significant gender * time interactions were detected for negative and general PANSS subscales, with the improvement being more pronounced for men. However, no differences were detected for the mean scores obtained during the study in any outcome measure, and the final profile was similar for men and women. Our results suggest that although the initial presentation of schizophrenia can differ according to gender, these differences are not sufficient enough to determine differentiated outcome 2 years after the initiation of treatment in non-substance-dependent patients. The influence of gender on the early course of schizophrenia does not seem to be clinically or functionally decisive in this population.