Inter old boy Goran Pandev ensured his former club's 2018 woes returned as Genoa secured a 2-0 victory at Stadio Luigi Ferraris.
The 34-year-old forward coolly dispatched the hosts' second goal in the 59th minute to land a sapping blow against Inter's bid for a Champions League place.
Luciano Spalletti's side won for the first time since the start of December when they beat Bologna 2-1 at San Siro last week but that result now appears to have been a false dawn.
Ivan Perisic joining Mauro Icardi on the injury list did little for their creative capabilities and Andrea Ranocchia's bizarre own-goal in first-half stoppage time left the Nerazzurri with an uphill task.
Pandev's goal means Inter lie fourth on the back of Roma's 2-0 win at Udinese earlier on Saturday and will drop out of the Champions League spots if Lazio beat Verona on Monday.
The veteran Macedonia international rolled back the years with a mazy run in the ninth minute, although the angle was against him by the time he managed to test Samir Handanovic.
Pandev unwittingly went closer shortly afterwards when his raking ball into the box bounced between Genoa midfielder Oscar Hiljemark and Handanovic and looped up to hit the crossbar.
Inter's first opening arrived in the 19th minute but Yann Karamoh's sliced finish was not a fitting way to greet Antonio Candreva's chipped cross after raiding into the Genoa box.
In the absence of Icardi and Perisic, Candreva looked the most likely Inter player to make something happen and the Italy winger forced Mattia Perin to save from a sweetly struck 31st-minute effort.
Ranocchia was already booked by the time he caught Andrej Galabinov with a flailing arm five minutes before half-time but referee Michael Fabbri elected not to consult VAR.
He might have been better receiving his marching orders because, on the stroke of the interval, Milan Skriniar clumped Ervin Zukanovic's cross against his centre-back partner and the ball flew past a helpless Handanovic.
Joao Cancelo got back to make a vital aerial challenge early in the second half when Pandev stole behind Ranocchia and looked poised to head home Aleandro Rosi's cross.
Just before the hour, Pandev got the goal his endeavours deserved. A wonderfully cushioned touch took the sting out of Diego Laxalt's speculative shot and he took the time and space it afforded him to calmly finish.
Spalletti sent on Rafinha in place of the ineffective Matias Vecino to try and force a response and Inter might have pulled a goal back when Roberto Gagliardini charged into the box to meet Cancelo's cross but glanced wide.
Karamoh was the Nerazzurri's match-winner last time out and, although he twisted skilfully past Genoa substitute Stephane Omeonga, he sent a vicious shot dipping narrowly over.
Zukanovic cleared a curling attempt from Eder off the line and might have added gloss to the scoreline for Serie A's 12th-placed side when he powered over from a corner, before Pandev took his standing ovation 10 minutes from time.
Key Opta Stats:
- Inter conceded more than one goal in a Serie A away game for the first time since last April (a 5-4 defeat away to Fiorentina).
- The last time Inter lost by a margin of two or more goals in a Serie A game away from home was in December 2016 (v Napoli).
- Goran Pandev has scored four goals in the league against Inter - two of these have come in the last two matches played between the sides at Genoa.
- The home side has won in each of the last 10 Serie A matches between Genoa and Inter.
- Genoa have won three consecutive Serie A games for the first time since May 2015 – on the previous occasion, the third success came against Inter.
- Antonio Candreva played his 300th Serie A game, while Danilo D'Ambrosio made his 150th appearance in the Italian top-flight.