Psychosocial treatments targeting the positive valence system (PVS) in depression and anxiety demonstrate efficacy in enhancing positive affect (PA), but response to treatment varies. We examined whether individual differences in neural activation to positive and negative valence incentive cues underlies differences in benefitting from a PVS-targeted treatment. Individuals with clinically elevated depression and/or anxiety (N = 88, ages 18 to 55) participated in one of two randomized, waitlist-controlled trials of Amplification of Positivity (AMP; NCT02330627, NCT03196544), a cognitive and behavioral intervention targeting the PVS. Participants completed a monetary incentive delay (MID) task during fMRI acquisition at baseline measuring neural activation to the possibility of gaining or losing money. Change in PA from before to after treatment was assessed using the Positive and Negative Affect Schedule. No significant associations were observed between baseline neural activation during gain anticipation and AMP-related changes in PA in regions of interest (striatum and insula) or whole-brain analyses. However, higher baseline striatal and insula activation during loss anticipation was associated with greater increases in PA post-AMP. This study provides preliminary evidence suggesting neural reactivity to negative valence cues may inform who stands to benefit most from treatments targeting the PVS. •Depression and anxiety disorders evince positive valence system (PVS) dysfunction.•Amplification of Positivity (AMP) is an emerging intervention targeting the PVS.•We examined neural predictors of change in positive affect after AMP.•Neural activation during gain anticipation did not predict outcomes.•Higher activation during loss anticipation predicted greater AMP treatment gains.