In routine practice, subjective response to antipsychotics is becoming a critical outcome measure among schizophrenia patients. This study sought to compare subjective response to atypical (risperidone and olanzapine) and typical antipsychotic drugs. Using a naturalistic cross-sectional design, we examined subjective response to antipsychotics (satisfaction with medication and subjective tolerability), psychopathology, side effects, emotional distress, and awareness in schizophrenia patients stabilized on atypical (n = 78) and typical (n = 55) drugs. Analysis of variance and multiple regression analysis were applied. We found that atypical drugs were superior to typical antipsychotics in both measures of subjective response, which were positively correlated (r = 0.52, P < 0.001). Poor subjective response was associated with severity of emotional distress, negative, and activation symptoms in the atypical group and with extrapyramidal side effects and positive symptoms in the typical group. Awareness of treatment is a positive factor that accounted for 20% and 34% of variation in the subjective responses to atypical and typical antipsychotic drugs, respectively. Demographic variables, age of onset, illness duration, and adjunctive drugs did not relate significantly to subjective response to antipsychotic drugs. Thus, atypical drugs are characterized by better subjective response compared with typical antipsychotics; their determinants differed considerably. Satisfaction with medication together with subjective tolerability needs to be considered in clinical trials.